| 1. |
- Björstad, Åse, 1976, et al.
(författare)
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The host defense peptide LL-37 selectively permeabilizes apoptotic leukocytes.
- 2009
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Ingår i: Antimicrobial agents and chemotherapy. - 1098-6596. ; 53:3, s. 1027-38
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Tidskriftsartikel (refereegranskat)abstract
- LL-37 is a cationic host defense peptide that is highly expressed during acute inflammation and that kills bacteria by poorly defined mechanisms, resulting in permeabilization of microbial membranes. High concentrations of LL-37 have also been reported to have cytotoxic effects against eukaryotic cells, but the peptide is clearly capable of differentiating between membranes with different compositions (eukaryotic versus bacterial membranes). Eukaryotic cells such as leukocytes change their membrane composition during apoptotic cell death, when they are turned into nonfunctional but structurally intact entities. We tested whether LL-37 exerted specific activity on apoptotic cells and found that the peptide selectively permeabilized the membranes of apoptotic human leukocytes, leaving viable cells unaffected. This activity was seemingly analogous to the direct microbicidal effect of LL-37, in that it was rapid, independent of known surface receptors and/or active cell signaling, and inhibitable by serum components such as high-density lipoprotein. A similar selective permeabilization of apoptotic cells was recorded for both NK cells and neutrophils. In the latter cell type, LL-37 permeabilized both the plasma and granule membranes, resulting in the release of both lactate dehydrogenase and myeloperoxidase. Apoptosis is a way for inflammatory cells to die silently and minimize collateral tissue damage by retaining tissue-damaging and proinflammatory substances within intact membranes. Permeabilization of apoptotic leukocytes by LL-37, accompanied by the leakage of cytoplasmic as well as intragranular molecules, may thus shift the balance between pro- and anti-inflammatory signals and in this way be of importance for the termination of acute inflammation.
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| 2. |
- Forsman, Huamei, et al.
(författare)
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Galectin 3 Aggravates Joint Inflammation and Destruction in Antigen-Induced Arthritis
- 2011
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Ingår i: ARTHRITIS AND RHEUMATISM. - : John Wiley and Sons, Ltd. - 0004-3591 .- 1529-0131. ; 63:2, s. 445-454
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Galectin 3, an endogenous beta galactoside-binding lectin, plays an important role in the modulation of immune responses. The finding that galectin 3 is present in the inflamed synovium in patients with rheumatoid arthritis suggests that the protein is associated with the pathogenesis of this disease. We undertook this study to investigate the influence of galectin 3 deficiency in a murine model of arthritis. Methods. Wild-type (WT) and galectin 3-deficient (galectin 3(-/-)) mice were subjected to antigen-induced arthritis (AIA) through immunization with methylated bovine serum albumin. The concentration of serum cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF alpha]) and antigen-specific antibodies was evaluated using a cytometric bead array platform and enzyme-linked immunosorbent assay (ELISA). Cellular IL-17 responses were examined by flow cytometry, ELISA, and enzyme-linked immunospot assay. Results. The joint inflammation and bone erosion of AIA were markedly suppressed in galectin 3(-/-) mice as compared with WT mice. The reduced arthritis in galectin 3(-/-) mice was accompanied by decreased levels of antigen-specific IgG and proinflammatory cytokines. The frequency of IL-17-producing cells in the spleen was reduced in galectin 3(-/-) mice as compared with WT mice. Exogenously added recombinant galectin 3 could partially restore the reduced arthritis and cytokines in galectin 3(-/-) mice. Conclusion. Our findings show that galectin 3 plays a pathogenic role in the development and progression of AIA and that the disease severity is accompanied by alterations of antigen-specific IgG levels, systemic levels of TNF alpha and IL-6, and frequency of IL-17-producing T cells. To our knowledge, this is the first report of in vivo evidence that galectin 3 plays a crucial role in the development of arthritis.
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| 3. |
- Forsman, Huamei, et al.
(författare)
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Reactivation of Desensitized Formyl Peptide Receptors by Platelet Activating Factor: A Novel Receptor Cross Talk Mechanism Regulating Neutrophil Superoxide Anion Production
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils express different chemoattractant receptors of importance for guiding the cells from the blood stream to sites of inflammation. These receptors communicate with one another, a cross talk manifested as hierarchical, heterologous receptor desensitization. We describe a new receptor cross talk mechanism, by which desensitized formyl peptide receptors (FPRdes) can be reactivated. FPR desensitization is induced through binding of specific FPR agonists and is reached after a short period of active signaling. The mechanism that transfers the receptor to a non-signaling desensitized state is not known, and a signaling pathway has so far not been described, that transfers FPRdes back to an active signaling state. The reactivation signal was generated by PAF stimulation of its receptor (PAFR) and the cross talk was uni-directional. LatrunculinA, an inhibitor of actin polymerization, induced a similar reactivation of FPRdes as PAF while the phosphatase inhibitor CalyculinA inhibited reactivation, suggesting a role for the actin cytoskeleton in receptor desensitization and reactivation. The activated PAFR could, however, reactivate FPRdes also when the cytoskeleton was disrupted prior to activation. The receptor cross talk model presented prophesies that the contact on the inner leaflet of the plasma membrane that blocks signaling between the G-protein and the FPR is not a point of no return; the receptor cross-talk from the PAFRs to the FPRdes initiates an actin-independent signaling pathway that turns desensitized receptors back to a signaling state. This represents a novel mechanism for amplification of neutrophil production of reactive oxygen species.
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| 4. |
- Sundqvist, Martina, et al.
(författare)
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Staphylococcus aureus-Derived PSMα Peptides Activate Neutrophil FPR2 but Lack the Ability to Mediate β-Arrestin Recruitment and Chemotaxis.
- 2019
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 203:12, s. 3349-3360
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Tidskriftsartikel (refereegranskat)abstract
- Formyl peptide receptor 2 (FPR2) is a G protein-coupled pattern recognition receptor sensing both mitochondrial- and bacterial-derived formylated peptides, including the PSMα toxins secreted by community-associated methicillin-resistant Staphylococcus aureus strains. Similar to many other FPR2 agonistic peptides, nanomolar concentrations of both PSMα2 and PSMα3 activate neutrophils to increase the cytosolic concentration of Ca2+ and release NADPH oxidase-derived reactive oxygen species. In addition, the PSMα peptides induce FPR2 homologous desensitization, actin polymerization, and neutrophil reactivation through a receptor cross-talk mechanism. However, in contrast to conventional FPR2 agonistic peptides, including the host-derived formyl peptide MCT-ND4, we found that the PSMα peptides lacked the ability to recruit β-arrestin and induce neutrophil chemotaxis, supporting the previous notion that β-arrestin translocation is of importance for cell migration. Despite the lack of β-arrestin recruitment, the PSMα peptides induced an FPR2-dependent ERK1/2 phosphorylation and internalization. Furthermore, structure-activity relationship analysis with PSMα2 derivatives revealed critical roles of the first 3 aa linked to N-fMet as well as the C terminus of PSMα2 in promoting FPR2 to recruit β-arrestin. In summary, our data demonstrate a novel neutrophil activation pattern upon FPR2 sensing of PSMα peptides, signified by the ability to induce increased intracellular Ca2+, ERK1/2 phosphorylation, internalization, and NADPH oxidase activity, yet lack of β-arrestin recruitment and neutrophil chemoattraction. These novel features adopted by the PSMα peptides could be of importance for S. aureus virulence and might facilitate identification of new therapeutic strategies for treating S. aureus infections.
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| 5. |
- Önnheim, Karin, et al.
(författare)
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A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide.
- 2014
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Ingår i: Experimental cell research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 323:1, s. 209-17
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils express several G-protein coupled receptors (GPCRs) and they cross regulate each other. We described a novel cross-talk mechanism in neutrophils, by which signals generated by the receptor for ATP (P2Y2) reactivate desensitized formyl peptide receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the cross-talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca(2+) transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel cross-talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP.
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| 6. |
- Ahlinder, J., et al.
(författare)
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Use of metagenomic microbial source tracking to investigate the source of a foodborne outbreak of cryptosporidiosis
- 2022
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Ingår i: FOOD AND WATERBORNE PARASITOLOGY. - : Elsevier. - 2405-6766. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Cryptosporidium is a protozoan parasite of global public health importance that causes gastroenteritis in a variety of vertebrate hosts, with many human outbreaks reported yearly, often from ingestion of contaminated water or food. Despite the major public health implications, little is typically known about sources of contamination of disease outbreaks caused by Cryptosporidium. Here, we study a national foodborne outbreak resulted from infection with Cryptosporidium parvum via romaine lettuce, with the main goal to trace the source of the parasite. To do so, we combined traditional outbreak investigation methods with molecular detection and characterization methods (i.e. PCR based typing, amplicon and shotgun sequencing) of romaine lettuce samples collected at the same farm from which the contaminated food was produced. Using 18S rRNA typing, we detected C. parvum in two out of three lettuce samples, which was supported by detections in the metagenome analysis. Microbial source tracking analysis of the lettuce samples suggested sewage water as a likely source of the contamination, albeit with some uncertainty. In addition, the high degree of overlap in bacterial species content with a public human gut microbial database corroborated the source tracking results. The combination of traditional and molecular based methods applied here is a promising tool for future source tracking investigations of food- and waterborne outbreaks of Cryptosporidium spp. and can help to control and mitigate contamination risks.
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| 7. |
- Andréasson, Emil, et al.
(författare)
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The Subcellular Localization of the Receptor for Platelet-Activating Factor in Neutrophils Affects Signaling and Activation Characteristics
- 2013
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Ingår i: Clinical & Developmental Immunology. - : Hindawi Limited. - 1740-2522 .- 1740-2530.
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Tidskriftsartikel (refereegranskat)abstract
- The localization in neutrophils, of the receptor for platelet-activating factor (PAFR), has been determined using subcellular fractionation and a receptor mobilization protocol. We show that the PAFR is expressed primarily in the plasma membrane. Although activation of neutrophils by PAF induces responses typical also of agonists that bind the formyl peptide receptors (FPR), known to be stored in mobilizable organelles, some quantitative as well as qualitative differences were observed when neutrophils were activated through these receptors. PAF is equipotent to fMLF (high affinity agonist for FPR1) to cleave off L-selectin and to induce granule/vesicle secretion but is more potent than fMLF to induce a rise in intracellular Ca2+. Similar to fMLF, PAF induced also a robust release of reactive oxygen species, but with higher EC50 value and was less sensitive to a PI3K inhibitor compared to the fMLF response. Despite the lack of a granule localized storage pool of receptors, the PAF-induced superoxide production could be primed; receptor mobilization was, thus, not required for priming of the PAF response. The desensitized PAFR could not be reactivated, suggesting that distinct signaling pathways are utilized for termination of the responses triggered through FPR1 and PAFR.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Björkman, Lena, 1965, et al.
(författare)
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Data on the NADPH-oxidase activity induced by WKYMVm and galectin-3 in bone marrow derived and exudated neutrophils isolated from four different mouse strains.
- 2017
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Ingår i: Data in brief. - : Elsevier BV. - 2352-3409. ; 10, s. 349-353
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are the key players in inflammatory reactions and the release of superoxide through the NADPH-oxidase upon neutrophil activation contributes to bacterial clearance and surrounding tissue damage. Here we describe data on the mouse neutrophil NADPH-oxidase activation induced by the mouse formyl peptide receptor (Fpr) agonist WKYMVm and galectin-3. Neutrophils isolated from bone marrow, peritoneal exudated, and in vitro TNFα primed bone marrow neutrophils from four different laboratory strains (C57BL/6, DBA/1, BALB/c and NMRI) were used. Both Fpr agonist and galectin-3 activated neutrophils to release superoxide. No differences were observed in the amounts of superoxide released from neutrophils derived from four different strains.
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| 12. |
- Björkman, Lena, 1965, et al.
(författare)
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Neutrophil recruitment to inflamed joints can occur without cellular priming.
- 2019
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Ingår i: Journal of leukocyte biology. - 1938-3673. ; 105:6, s. 1123-1130
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Tidskriftsartikel (refereegranskat)abstract
- Recruitment of neutrophils from blood to tissues is a cardinal event in inflammation during which neutrophils switch from a resting, naive state to a preactivated, primed phenotype; the priming process is characterized by alterations in the composition of cell surface adhesins, for example, shedding of l-selectin and mobilization of granule-stored integrins to the cell surface. Ligation of chemotactic receptors and interactions with the endothelial lining are established triggers of neutrophil priming and in line with this, in vivo transmigrated neutrophils obtained from tissues are typically highly primed. We here characterize the priming of neutrophils brought about by in vivo recruitment from blood to inflamed joints by the analyses of synovial fluid and blood from patients with inflammatory arthritis. For comparisons, we used controlled in vivo models of neutrophil transmigration to skin of healthy subjects. In contrast to the residing view and in vivo transmigrated neutrophils from skin models, neutrophils from synovial fluid were often surprisingly resting and phenotypically very similar to naive cells isolated from peripheral blood; synovial fluid cells often retained l-selectin and had undergone minimal up-regulation of integrin receptors. In complete agreement with our in vivo findings, cell-free synovial fluid was potently chemotactic without triggering alteration of surface receptors also in vitro. We conclude that tissue recruitment of neutrophils does not by default trigger l-selectin shedding and granule mobilization, and the chemoattractant(s) guiding neutrophils to synovial fluid apparently operate without inducing cellular priming.
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| 13. |
- Björnsdottir, Halla, et al.
(författare)
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Phenol-soluble Modulin α Peptide Toxins from aggressive Staphylococcus aureus induce rapid Formation of neutrophil extracellular Traps through a reactive Oxygen species-independent Pathway
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin alpha (PSM alpha) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMa-induced NETs contained the typical protein markers and were able to capture microbes. The PSMa-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase-negative Candida albicans. Opposed to classic NETosis, PSMa-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4 degrees C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMa peptides, a process that may be of importance for CA-MRSA virulence.
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| 14. |
- Bodin, Theo, et al.
(författare)
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Activity in neck-shoulder and lower arm muscles during computer and smartphone work
- 2019
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Ingår i: International Journal of Industrial Ergonomics. - : ELSEVIER. - 0169-8141 .- 1872-8219. ; 74
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Tidskriftsartikel (refereegranskat)abstract
- Relevance to industry: There is emerging evidence of musculoskeletal problems related to smartphone work and a rapid transition to mobile workplaces, where smartphones are key working tools. Aim: The study's aim was to compare muscle activity during computer work with smartphone work and to see what possible effects ergonomic recommendations for smartphone usage have on muscle activity. Methods: Activity was measured bilaterally from the upper trapezius muscle and from lower arm muscles on the right hand side, on twelve participants with surface electromyography who performed e-mail work on the computer using ergonomic recommendations, smartphone in a self-chosen way of working and on smartphone with ergonomic recommendations. Effects on productivity was not assessed in this study. Results: Activity in m. trapezius and m. extensor digitorum was significantly higher during computer work (p < 0.05) than during the two smartphone usages and activity in m. interossei dorsalis 1 was, vice versa, significantly higher during smartphone work fp < 0.05). Comparison of smartphone in self-chosen way of working and smartphone with ergonomic recommendations showed no significant differences. Conclusions: Previous research has highlighted the benefits of variation of work postures. This paper indicates that replacing the computer with a smartphone gives the trapezius muscle an opportunity to rest.
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| 15. |
- Brindefalk, B., et al.
(författare)
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Bacterial composition in Swedish raw drinking water reveals three major interacting ubiquitous metacommunities
- 2022
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Ingår i: Microbiologyopen. - : Wiley. - 2045-8827. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Background Surface raw water used as a source for drinking water production is a critical resource, sensitive to contamination. We conducted a study on Swedish raw water sources, aiming to identify mutually co-occurring metacommunities of bacteria, and environmental factors driving such patterns. Methods The water sources were different regarding nutrient composition, water quality, and climate characteristics, and displayed various degrees of anthropogenic impact. Water inlet samples were collected at six drinking water treatment plants over 3 years, totaling 230 samples. The bacterial communities of DNA sequenced samples (n = 175), obtained by 16S metabarcoding, were analyzed using a joint model for taxa abundance. Results Two major groups of well-defined metacommunities of microorganisms were identified, in addition to a third, less distinct, and taxonomically more diverse group. These three metacommunities showed various associations to the measured environmental data. Predictions for the well-defined metacommunities revealed differing sets of favored metabolic pathways and life strategies. In one community, taxa with methanogenic metabolism were common, while a second community was dominated by taxa with carbohydrate and lipid-focused metabolism. Conclusion The identification of ubiquitous persistent co-occurring bacterial metacommunities in freshwater habitats could potentially facilitate microbial source tracking analysis of contamination issues in freshwater sources.
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| 16. |
- Bylund, Johan, 1975, et al.
(författare)
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Turning Chemoattractant Receptors On and Off with Conventional Ligands and Allosteric Modulators: Recent advances in formyl peptide receptor signaling and regulation
- 2014
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Ingår i: Inflammation and cell signaling. - : Smart Science and Technology, LLC. - 2330-7803 .- 2330-7803 .- 2330-779X. ; 1:1
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Forskningsöversikt (refereegranskat)abstract
- Recruitment and activation of neutrophils at sites of infection/inflammation relies largely on the surface expression of G-protein coupled receptors (GPCRs) that recognize chemoattractants. One of these receptors, FPR1, for which formylated peptides generated by bacteria and mitochondria are high affinity agonists, was among the first human neutrophil GPCR to being cloned. This receptor shares large sequence homologies with FPR2, another member of the FPR-family expressed in human neutrophils and having a distinct ligand binding profile. The two FPRs transduce very similar neutrophil responses but possess somewhat different regulatory profiles. The FPRs have served as excellent model receptors in studies attempting to understand not only GPCR related regulation in general, but also receptor signaling in relation to innate immune reactivity and inflammation. Recent research has identified not only a large number of conventional ligands (agonist/antagonists) that regulate FPR activities by binding to surface exposed parts of the receptors, but also a number of membrane penetrating molecules that allosterically modulate receptor function after passing the membrane and interacting with the receptor on the cytosolic side. After activation, FPR signaling is rapidly terminated and the receptors become desensitized, a dormant state that can be achieved by multiple mechanisms. A coupling of the activated receptors to the actin cytoskeleton in a process that physically separates the receptors from the signaling G-protein is one such mechanism. Traditionally, the desensitized state has been viewed as a point of no return, but recent findings challenge this view and demonstrate that desensitized FPRs may in fact be reactivated to resume active signaling. The FPRs have also the capacity to communicate with other receptors in a hierarchical manner and this receptor cross-talk can both dampen and amplify neutrophil responses. In this review, we summarize some recent advances of our understanding how the FPRs can be turned on and off and discuss some future challenges, including mechanisms of allosteric modulation, receptor cross-talk, and FPR reactivation.
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| 17. |
- Camponeschi, Alessandro, et al.
(författare)
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Human CD38 regulates B cell antigen receptor dynamic organization in normal and malignant B cells.
- 2022
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:9
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Tidskriftsartikel (refereegranskat)abstract
- CD38 is a multifunctional protein expressed on the surface of B cells in healthy individuals but also in B cell malignancies. Previous studies have suggested a connection between CD38 and components of the IgM class B cell antigen receptor (IgM-BCR) and its coreceptor complex. Here, we provide evidence that CD38 is closely associated with CD19 in resting B cells and with the IgM-BCR upon engagement. We show that targeting CD38 with an antibody, or removing this molecule with CRISPR/Cas9, inhibits the association of CD19 with the IgM-BCR, impairing BCR signaling in normal and malignant B cells. Together, our data suggest that CD38 is a new member of the BCR coreceptor complex, where it exerts a modulatory effect on B cell activation upon antigen recognition by regulating CD19. Our study also reveals a new mechanism where α-CD38 antibodies could be a valuable option in therapeutic approaches to B cell malignancies driven by aberrant BCR signaling.
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| 18. |
- Dahlstrand Rudin, Agnes, et al.
(författare)
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Porphyromonas gingivalis Produce Neutrophil Specific Chemoattractants Including Short Chain Fatty Acids
- 2021
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Ingår i: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil migration from blood to tissue-residing microbes is governed by a series of chemoattractant gradients of both endogenous and microbial origin. Periodontal disease is characterized by neutrophil accumulation in the gingival pocket, recruited by the subgingival biofilm consisting mainly of gram-negative, anaerobic and proteolytic species such as Porphyromonas gingivalis. The fact that neutrophils are the dominating cell type in the gingival pocket suggests that neutrophil-specific chemoattractants are released by subgingival bacteria, but characterization of chemoattractants released by subgingival biofilm species remains incomplete. In the present study we characterized small (< 3 kDa) soluble chemoattractants released by growing P. gingivalis, and show that these are selective for neutrophils. Most neutrophil chemoattractant receptors are expressed also by mononuclear phagocytes, the free fatty acid receptor 2 (FFAR2) being an exception. In agreement with the selective neutrophil recruitment, the chemotactic activity found in P. gingivalis supernatants was mediated in part by a mixture of short chain fatty acids (SCFAs) that are recognized by FFAR2, and other leukocytes (including monocytes) did not respond to SCFA stimulation. Although SCFAs, produced by bacterial fermentation of dietary fiber in the gut, has previously been shown to utilize FFAR2, our data demonstrate that the pronounced proteolytic metabolism employed by P. gingivalis (and likely also other subgingival biofilm bacteria associated with periodontal diseases) may result in the generation of SCFAs that attract neutrophils to the gingival pocket. This finding highlights the interaction between SCFAs and FFAR2 in the context of P. gingivalis colonization during periodontal disease, but may also have implications for other inflammatory pathologies involving proteolytic bacteria.
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| 19. |
- Forsman, Huamei, et al.
(författare)
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Receptor-Dependent and -Independent Immunomodulatory Effects of Phenol-Soluble Modulin Peptides from Staphylococcus aureus on Human Neutrophils Are Abrogated through Peptide Inactivation by Reactive Oxygen Species
- 2012
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Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 80:6, s. 1987-1995
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Tidskriftsartikel (refereegranskat)abstract
- The virulence and pathogenesis mechanisms of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains depend on a newly described group of phenol-soluble modulin (PSM) peptides (the PSM alpha peptides) with cytolytic activity. These toxins are alpha-helical peptides with a formyl group at the N terminus, and they activate neutrophils through formyl peptide receptor 2 (FPR2), a function closely correlated to the capacity of staphylococcal species to cause invasive infections. The effects of two synthetic PSM alpha peptides were investigated, and we show that they utilize FPR2 and promote neutrophils to produce reactive oxygen species (ROS) which in turn trigger inactivation of the peptides. Independently of FPR2, the PSM alpha peptides also downregulate the neutrophil response to other stimuli and exert a cytolytic effect to which apoptotic neutrophils are more sensitive than viable cells. The novel immunomodulatory functions of the PSM alpha peptides were sensitive to ROS generated by the neutrophil myeloperoxidase (MPO)-H2O2 system, suggesting a role for this enzyme system in counteracting bacterial virulence.
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| 20. |
- Forsman, Huamei, et al.
(författare)
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The beta-galactoside binding immunomodulatory lectin galectin-3 reverses the desensitized state induced in neutrophils by the chemotactic peptide f-Met-Leu-Phe: role of reactive oxygen species generated by the NADPH-oxidase and inactivation of the agonist
- 2008
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 18:11, s. 905-12
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils interacting with a chemoattractant gradually become nonresponsive to further stimulation by the same agonist, a process known as desensitization. Receptor desensitization is a highly regulated process that involves different mechanisms depending on which receptor-ligand pair that is studied. Galectin-3, a member of a large family of beta-galactoside-binding lectins, has been suggested to be a regulator of the inflammatory process, augmenting or directly triggering the neutrophil functional repertoire. We show here that the desensitized state of neutrophils interacting with the chemotactic peptide fMLF is broken by galectin-3 and that this is achieved through an oxygen radical-mediated inactivation of the chemoattractant. The effect was inhibited by the competitor lactose and required the affinity of galectin-3 for N-acetyllactosamine, a saccharide typically found on cell surface glycoproteins. The latter was shown using a galectin-3 mutant that lacked N-acetyllactosamine binding activity, and this protein was not active. The mechanism behind the inactivation of the chemoattractant was found to depend on the ability of galectin-3 to induce a neutrophil generation/secretion of reactive oxygen species which in combined action with myeloperoxidase inactivated the peptides.
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| 21. |
- Forsman, Huamei, et al.
(författare)
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WHAT FORMYL PEPTIDE RECEPTORS, IF ANY, ARE TRIGGERED BY COMPOUND 43 AND LIPOXIN A(4) ?
- 2011
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Ingår i: Scandinavian journal of immunology. - : Wiley. - 1365-3083 .- 0300-9475.
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Tidskriftsartikel (refereegranskat)abstract
- In this study we determined receptor preferences for compound 43, a nitrosylated pyrazolone derivative, and the eicosanoid lipoxin A(4) (LXA(4) ), potent anti-inflammatory mediators in many experimental in vivo models Their effects have been suggested to be mediated through binding to FPR2 (earlier known as FPRL1 or ALXR), one of the two members of the formyl peptide receptor family expressed in neutrophils. Compound 43 activates all neutrophil functions investigated whereas LXA(4) induces a unique inhibiting pathway suggested to involve β-arrestin binding as an early signaling step, but not a transient rise in intracellular Ca(2+) . We show that compound 43 can activate not only FPR2 but also FPR1 the other neutrophil receptor in the FPR family, and FPR1 is actually the preferred receptor in human neutrophils and possibly also in the murine equivalent. LXA(4) analogues from two commercial sources were used, and neither of these induced any translocation of β-arrestin as measured in an enzyme-fragment-complementation assay. The conclusions drawn from these experiments are that neither compound 43 nor LXA(4) work as FPR2 agonists in neutrophils, findings of importance for a proper interpretation of results obtained with these compounds as regulators of inflammation.
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| 22. |
- Forsman, Jonas, et al.
(författare)
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Selective serotonin re-uptake inhibitors and the risk of violent suicide: a nationwide postmortem study
- 2019
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Ingår i: European Journal of Clinical Pharmacology. - : SPRINGER HEIDELBERG. - 0031-6970 .- 1432-1041. ; 75:3, s. 393-400
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Tidskriftsartikel (refereegranskat)abstract
- PurposeWe endeavored to investigate whether previous findings of an association between antemortem exposure to selective serotonin re-uptake inhibitors (SSRI) and method of suicide could be replicated.MethodsUsing the Swedish National Board of Forensic Medicines toxicology database and the Swedish National Board of Health and Welfares national registries of causes of death and prescriptions, 10,002 incidents of suicide were retrieved. Risks of violent suicide conferred by SSRIs, expressed as odds ratios (ORs) with 95% confidence intervals (CIs), were estimated using logistic regression. In accordance with previous work, suicide by violent meanscaseswere defined as death attributable to causes designated by ICD-10 codes X70-X83 and Y20-Y33; and suicide by non-violent meanscontrolsby codes X60-X69 and Y10-Y19.ResultsOur results imply that SSRI exposure confers a risk of violent suicide for shorter treatment durations; and that antemortem exposure to other substances (including illegal drugs) confounds estimates of risk. After adjustment for age, sex, and other substances, SSRIs treatment not exceeding 28days conferred an almost fourfold risk of violent suicide (OR 3.6 [95% CI 1.9-6.8]), a finding partly in line with a recent Swedish study that employed a case-crossover design.ConclusionsAlthough risks associated with shorter treatment duration may reflect latencies to onset of therapeutic effect, it is unclear how latencies would influence the choice of suicide method, unless conditions for which SSRIs are prescribed are themselves associated with violent suicide. Finally, in the total dataset, SSRIs were not associated with an increased risk of violent suicide; however, by adjusting for other substances, we avoided the spurious conclusion that the effect of medications in this regard is protective.
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| 23. |
- Forsman, Karin
(författare)
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Fracture behaviour of acetylated wood : Material characterisation and dowel-type connections
- 2020
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In order to increase the competitiveness of timber as a building material in outdoor applications, durability and dimensional stability must be ensured. Acetylation enables an environmentally friendly way to increase both durability and dimensional stability of wood, without introducing harmful substances to the environment. The focus of the present research is to examine the possibility of adding a structural value by acetylation of wood species native to the Nordic region, rarely used for loadbearing structures outdoors due to poor durability and dimensional stability. Yet, before a large scale use is possible, the mechanical properties of acetylated wood must be examined. The research presented in this dissertation focuses on the brittleness of acetylated wood, both at a clear wood level as well as in structural applications.Fracture characteristics are hereby defined by properties that influence the brittleness, considered by the stiffness, tensile strength and fracture energy. For Scots pine conditioned at a relative humidity of 60% and a temperature of 20◦C, no significant impact of the acetylation process was found for the stiffness along the grain, nor for the tensile strength perpendicular to the grain. However, for Scots pine and birch examined at various relative humidity levels, the fracture energy was found to be significantly reduced for acetylated wood at relative humidity levels up to 97%. The largest difference between unmodified and acetylated wood of the same species and at equal climate conditions was approximately 50%. The studies demonstrated a clear moisturedependencyof the fracture energy for both unmodified and acetylated wood, but it was suggested that the fracture energy is lower for acetylated wood compared to unmodified wood at similar moisture contents. The lower fracture energy of acetylated wood when compared to unmodified wood at equal relative humidity levels can thus partly, but not solely, be explained by the reduced hygroscopicity of acetylated wood.To evaluate the implications of the increased brittleness in terms of structural applications, single doweltype connections made from acetylated and unmodified Scots pine were studied. Results were compared to Eurocode 5 estimations to evaluate the validity of current design provisions for acetylated wood. It was found that, for all the tested enddistances for loading parallel to the grain, joints made from acetylated wood failed in a brittle manner. Nevertheless, connections made from acetylated wood demonstrated a significantly higher embedment strength and loadbearing capacity parallel to the grain, and Eurocode 5 provided conservative estimations. For loading perpendicular to the grain, a reduced splitting capacity was found for acetylated wood compared to unmodified wood, and here the loadbearing capacity wasoverestimated by Eurocode 5.The most important conclusion from the research presented herein is the increased brittleness of acetylated wood compared to unmodified wood. Special attention is, hence, required in structural design using acetylated Scots pine and birch. In case of doweltype connections, or other loading situations where stress concentrations occur, measures should be taken to avoid premature brittle failure modes. This risk may for instance be limited by increasingm spacings between fasteners as well as endand edgedistances, and/or reinforcement of joints. Further studies are needed to increase the knowledge of how the acetylation process will impact loadbearing structures. Although the research presented herein reveals one disadvantage with acetylated wood, it can still outperform unmodified wood in moist conditions thanks to e.g. increased dimensional stability and durability.
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| 24. |
- Forsman, Karin, et al.
(författare)
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Fracture characteristics of acetylated young Scots pine
- 2020
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Ingår i: European Journal of Wood and Wood Products. - : Springer Science and Business Media LLC. - 0018-3768 .- 1436-736X. ; 78:4, s. 693-703
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Tidskriftsartikel (refereegranskat)abstract
- A study on the fracture characteristics of unmodified and chemically modified Scots pine (Pinus sylvestris) is presented. The investigated material consisted of small-dimension sawn timber originating from young logs (thinnings), aged 30–40 years. The modified samples were acetylated with acetic anhydride in an industrial scale process without the use of any catalyst, reaching an acetyl content of approximately 20%. Clear wood specimens, consisting of either heartwood or sapwood, were extracted and conditioned to equilibrium at a relative humidity of 60% and a temperature of 20 °C. The fracture energy for mode I loading in tension perpendicular to the grain was determined using single edge notched beam (SENB) specimens, subjected to three-point bending. Additionally, the modulus of elasticity along the grain and the tensile strength perpendicular to the grain were determined for sapwood specimens. The findings demonstrated a significant decrease (between 36 and 50%) in the fracture energy for the acetylated specimens, compared to the unmodified specimens. No significant effect of the acetylation process on the modulus of elasticity, nor on the tensile strength could be concluded. This study indicates that the acetylation process used results in an increased brittleness for Scots pine. Further studies are needed to analyse why the fracture energy is impaired, and to examine whether and how current timber engineering design provisions can or should be revised to account for the increased brittleness of acetylated Scots pine.
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| 25. |
- Forsman, Karin, et al.
(författare)
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Impact of Acetylation on the Behaviour of Single-Dowel Timber Connections
- 2024
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Ingår i: Buildings. - 2075-5309. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents an experimental study where the mechanical behaviour of single-dowel timber connections made of acetylated Scots pine is compared with the behaviour of connections made from untreated Scots pine. The main aim was to evaluate the influence of the acetylation on the connection brittleness and also to compare the experimental results to the design provisions of the current European structural timber code, Eurocode 5 (EC5). The experiments included embedment tests and tests with connections loaded parallel and perpendicular to the grain, and, for the latter tests, applying different end and edge distances. The acetylated wood showed a 2% increase in density and a 31% increase in embedment strength compared to the untreated wood. For tests on connections loaded parallel to the grain, all specimens made from acetylated wood failed in a brittle manner, while the connections made from untreated wood and complying with minimum end distance of the EC5 design provisions failed due to embedment failure followed by splitting involving cracking along the grain. The connections made of acetylated wood showed a 13–15% higher capacity than the corresponding specimens made from untreated wood. Thus, to fully utilize the potential of the increased embedment strength parallel to the grain, it is concluded that reinforcement of the joint, e.g., by self-tapping screws or externally applied sheet reinforcement would be necessary if the minimum end distances of EC5 are applied. The current design provisions for loading perpendicular to the grain overestimated the capacities severely with predicted characteristic values being 20–50% higher than mean values from tests for the recommended minimum edge distances. Finally, it was found that the splitting capacity in loading perpendicular to the grain was 10–18% lower for the specimens made from acetylated wood compared to the untreated wood.
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| 26. |
- Forsman, Karin, et al.
(författare)
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Moisture-dependency of the fracture energy of wood : A comparison of unmodified and acetylated Scots pine and birch
- 2021
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Ingår i: Holzforschung. - : Walter de Gruyter GmbH. - 0018-3830 .- 1437-434X. ; 75:8, s. 731-741
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Tidskriftsartikel (refereegranskat)abstract
- The moisture-dependency of the fracture energy for unmodified and acetylated Scots pine (Pinus sylvestris L.) and birch (Betula pendula Roth) has been investigated. Specimens were conditioned at relative humidity levels of 20, 75, and 97%, as well as dry and water-saturated. At moisture contents below 15%, the fracture energy increased with increasing moisture content for both unmodified and acetylated wood, while it decreased for untreated wood at higher moisture contents. A significant difference in moisture-dependency was found, indicating higher fracture energy for unmodified wood compared to acetylated wood at similar moisture contents. Additionally, to assess the impact of the increased brittleness for structural applications, the fracture energy was compared at equal relative humidity levels. The largest difference was seen at 75% relative humidity with approximately 50% lower fracture energy for acetylated wood. No significant differences were found for water-saturated samples. The moisture-dependency of the fracture energy, combined with the reduced hygroscopicity of acetylated wood, is suggested to be one, but not the only, contributing factor to the lower fracture energy of acetylated wood compared to unmodified wood at equal humidity levels. These observations have importance for structural design since design codes often assess material parameters based on ambient humidity.
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| 27. |
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| 28. |
- Gabl, Michael, et al.
(författare)
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Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties.
- 2018
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Ingår i: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 200:9, s. 3269-3282
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Tidskriftsartikel (refereegranskat)abstract
- Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA-encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA-encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochromebprefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of β-arrestin. In summary, we identify several novel FPR-activating peptides with sequences present in the N termini of mitochondrial DNA-encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs.
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| 29. |
- Hardy, J, et al.
(författare)
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Professional development policy and politics across international contexts: from mutuality to measurability?
- 2010
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Ingår i: Pedagogy, Culture & Society. - 1468-1366. ; 18:1, s. 81-92
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Tidskriftsartikel (refereegranskat)abstract
- This article reveals how educational policies and policy contexts in Sweden, Norway, Finland and Australia establish the circumstances which enable and constrain individual and collective teacher professional development as praxis. We provide insights into existing partnerships between universities and schools, and, municipalities and the state as vehicles for professional development, and the way in which policy contexts have shaped and reshaped these relationships. We also consider the resonances, and points of tension, across and within different national policy settings, to assist us to understand, and to productively inform, policy-making within and across national contexts. We conclude by arguing that while professional development policies within and across international contexts are productive of teachers’ collective focus upon student learning – a form of ‘mutuality’ – they increasingly serve as overarching practices which contribute to the development of educational practices reflective of national and i
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| 30. |
- Hägglund, Moa, et al.
(författare)
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Accounting for bacterial overlap between raw water communities and contaminating sources improves the accuracy of signature-based microbial source tracking
- 2018
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Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Microbial source tracking (MST) analysis is essential to identifying and mitigating the fecal pollution of water resources. The signature-based MST method uses a library of sequences to identify contaminants based on operational taxonomic units (OTUs) that are unique to a certain source. However, no clear guidelines for how to incorporate OTU overlap or natural variation in the raw water bacterial community into MST analyses exist. We investigated how the inclusion of bacterial overlap between sources in the library affects source prediction accuracy. To achieve this, large-scale sampling-including feces from seven species, raw sewage, and raw water samples from water treatment plants - was followed by 16S rRNA amplicon sequencing. The MST library was defined using three settings: (i) no raw water communities represented; (ii) raw water communities selected through clustering analysis; and (iii) local water communities collected across consecutive years. The results suggest that incorporating either the local background or representative bacterial composition improves MST analyses, as the results were positively correlated to measured levels of fecal indicator bacteria and the accuracy at which OTUs were assigned to the correct contamination source increased fourfold. Using the proportion of OTUs with high source origin probability, underpinning a contaminating signal, is a solid foundation in a framework for further deciphering and comparing contaminating signals derived in signature-based MST approaches. In conclusion, incorporating background bacterial composition of water in MST can improve mitigation efforts for minimizing the spread of pathogenic and antibiotic resistant bacteria into essential freshwater resources.
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| 31. |
- Ottosson, Jakob, et al.
(författare)
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Bevattningsvatten : kunskapsunderlag
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Livsmedel från växtriket kan i vissa fall sprida mikrobiologisk smitta. Bär, bladgrönt och groddarmedför en särskild risk. Det beror på att de ofta äts råa eller efter minimal tillredning. Vi värmer deminte innan vi äter dem.Om livsmedlen är kontaminerade är det med stor sannolikhet orsakat av bevattningen. Vattnet kan havarit påverkat av avföring. Det kan också bero på spillning från vilda djur. Även naturgödsel kanförorena produkterna vid stänk från jord.Syftet med detta projekt var att se över kvaliteten på vatten för bevattning i Sverige. Vi ville koppladet till mikrobiologiska risker och utifrån det ta fram underlag till nationella råd och riktlinjer. Måletär ”en säkrare produktion av ätfärdiga bär och grönsaker som bättre förebygger sjukdomsutbrott”.Det visade sig att kvaliteten på vattnet generellt sett var god hos odlarna i projektet. Det samma gällergrödor. I vatten hittade vi enstaka sjukdomsframkallande mikroorganismer och ESBL-bildande E. coli.Dessa hittade vi dock endast i ytvatten som var mer förorenade av avföring och spillning. Men endastett fåtal prov på gröda visade på högre fekal förorening. Majoriteten av dessa kom från en och sammaodlare, som bevattnade med vatten från en damm. Vi hittade inga patogener på grödor. Däremot var ettprov på vitkål positivt för ESBL-bildande E. coli.Vi gjorde en kvantitativ riskvärdering av Shigatoxinproducerande E. coli (STEC) från isbergssallat.Den visade att även en liten förorening orsakad av avföring och utan påvisade STEC-bakterier ibevattningsvattnet kan utgöra en risk för mag-och tarminfektion. Riskvärderingen kan användas somunderlag för att föreslå mikrobiologiska kriterier, till exempel på vattenkvalitet. Vi behöver dockbeakta osäkerheterna med värderingen. De viktigaste osäkerheterna var utsöndringen av ochpatogeniciteten hos STEC från infekterade nötkreatur. Hur mycket av dessa fastnar på den bevattnadegrödan? Hur stor är sannolikheten att infekteras vid låga doser (enstaka STEC-bakterier)? Och hur storär risken av stänk från jord?Det finns olika åtgärder att ta till för att minska sannolikheten för utbrott och sjukdomsfall. Dessa är 1.Kriterier för vattenkvalitet. 2: Rening av vatten som inte uppnår dessa kriterier. 3. Införa enuppehållstid mellan sista bevattning och skörd. 4. Dessutom kan konsumenterna skölja produkternainnan de konsumerar dem. Det är också viktigt att se till att hålla utrustningen ren, exempelvis rör ochmunstycken. På så vis undviks föroreningar och tillväxt av bakterier.Om ytvatten måste användas för bevattning under de sista två veckorna innan skörd bör ettprovtagningsprogram utformas. Proven bör då visa på låg fekal förorening samt avsaknad avSalmonella. I bästa fall bör ytvatten renas före bevattning. Detta kan göras till exempel med hjälp avfotokatalys, UV-ljus eller filtrering. De sista två dagarna före skörd bör dock endast vatten avdricksvattenkvalitet användas.I en framtid med sjunkande grundvattennivåer, torrare somrar och blötare vintrar finns ett behov av attsamla in vatten för bevattning. Det bör göras under höstregn och vårfloder, samt vintertid. Vattnet fårsedan lagras i magasin. Vatten från bevattningsmagasin kan behöva renas innan det används förbevattning beroende på hur skyddat magasinet är från föroreningar.
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| 32. |
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| 33. |
- Pullerits, Kristjan, et al.
(författare)
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Impact of UV irradiation at full scale on bacterial communities in drinking water
- 2020
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Ingår i: npj Clean Water. - : Springer Science and Business Media LLC. - 2059-7037. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Water in a full-scale drinking water treatment plant was irradiated with ultraviolet (UV) doses of 250, 400, and 600 J/m2, and the effect on bacterial communities investigated using 16s rRNA gene amplicon sequencing, heterotrophic plate counts (HPCs), coliform, and Escherichia coli counts. The bacteria in the irradiated water were also analyzed following storage for 6 days at 7 °C, to approximate the conditions in the distribution system. The log10 reduction of HPCs at 400 J/m2 was 0.43 ± 0.12. Phylogenetic examination, including DESeq2 analysis, showed that Actinobacteria was more resistant to UV irradiation, whereas Bacteroidetes was sensitive to UV. Phylum Proteobacteria contained monophyletic groups that were either sensitive or resistant to UV exposure. The amplicon sequence variants (ASVs) resistant to UV irradiation had a greater average GC content than the ASVs sensitive to UV, at 55% ± 1.7 (n = 19) and 49% ± 2.5 (n = 16), respectively. Families Chitinophagaceae, Pelagibacteraceae, Holophagaceae, Methylophilaceae, and Cytophagaceae decreased linearly in relative abundance, with increasing UV dose (P < 0.05, Pearson’s correlation). When irradiated water was stored, Chitinophagaceae, Comamonadaceae, and Flavobacteriaceae families decreased in relative abundance, whereas ACK-M1, Mycobacteriaceae, and Nitrosomonadaceae were increasing in relative abundance. This suggests that the impact of UV irradiation cannot only be considered directly after application but that this treatment step likely continues to influence microbial dynamics throughout the distribution system.
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| 34. |
- Rönnerman, Karin, 1952, et al.
(författare)
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Professionell och didaktisk utveckling genom aktionsforskning
- 2011
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Ingår i: Hansén, S-E. & Forsman, L. Allmändidaktik- vetenskap för lärare. - Lund : Studentlitteratur. - 9789144057835 ; , s. 377-392
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- 2000-talets lärare har press på sig att undervisningen ska leda till att elever presterar bra i de jämförelser som görs nationellt mellan skolor och internationellt mellan länder. Politikers bedömning är att eleverna borde nå bättre resultat och det orsakar vanligtvis omedelbara åtgärder i form av olika satsningar på kompetensutveckling där specifika ämnen eller områden, t.ex. matematik, läsning och skrivning, är i fokus. Kompetensutveckling av detta slag består ofta av punktinsatser med syftet att åtgärda ”brister” hos lärarna. Självklart ska lärare behärska dessa ämneskunskaper, men de lärare vi samtalat med anser snarare att det är tid för pedagogiska samtal som gynnar utvecklingen av vardagsarbetet och professionen.
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| 35. |
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| 36. |
- Strid Holmertz, Alexander, et al.
(författare)
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Data describing expression of formyl peptide receptor 2 in human articular chondrocytes
- 2020
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 31
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Tidskriftsartikel (refereegranskat)abstract
- The formyl peptide receptor 2 (FPR2) belongs to the family of seven-transmembrane G protein-coupled receptors (GPCR) and are expressed by many different cells but mainly studied in immune cells. FPR2 is involved in host defense against bacterial infections and clearance of damaged cells through the oxidative burst and chemotaxis of neutrophils. In addition, FPR2 has also been implicated as an immunomodulator in sterile inflammations, e.g. inflammatory joint diseases. Here we present data regarding FPR2 expression in human articular chondrocytes, isolated from healthy individuals and osteoarthritic patients, on both mRNA and protein level using qPCR and Imagestream flow cytometry. We also present data after receptor stimulation and monitoring of production of nitric oxide, reactive oxygen species, IL-6, IL-8 and MMP-3. The presented data show that human articular chondrocytes from patients with osteoarthritis as well as from healthy individuals express FPR2 both at mRNA and protein level. The biological relevance of FPR2 expression in chondrocytes needs to be further investigated. (c) 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
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| 37. |
- Sundqvist, Martina, et al.
(författare)
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Similarities and differences between the responses induced in human phagocytes through activation of the medium chain fatty acid receptor GPR84 and the short chain fatty acid receptor FFA2R.
- 2018
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Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1865:5, s. 695-708
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Tidskriftsartikel (refereegranskat)abstract
- GPR84 is a recently de-orphanized member of the G-protein coupled receptor (GPCR) family recognizing medium chain fatty acids, and has been suggested to play important roles in inflammation. Due to the lack of potent and selective GPR84 ligands, the basic knowledge related to GPR84 functions is very limited. In this study, we have characterized the GPR84 activation profile and regulation mechanism in human phagocytes, using two recently developed small molecules that specifically target GPR84 agonistically (ZQ16) and antagonistically (GLPG1205), respectively. Compared to our earlier characterization of the short chain fatty acid receptor FFA2R which is functionally expressed in neutrophils but not in monocytes, GPR84 is expressed in both cell types and in monocyte-derived macrophages. In neutrophils, the GPR84 agonist had an activation profile very similar to that of FFA2R. The GPR84-mediated superoxide release was low in naïve cells, but the response could be significantly primed by TNFα and by the actin cytoskeleton disrupting agent Latrunculin A. Similar to that of FFA2R, a desensitization mechanism bypassing the actin cytoskeleton was utilized by GPR84. All ZQ16-mediated cellular responses were sensitive to GLPG1205, confirming the GPR84-dependency. Finally, our data of in vivo transmigrated tissue neutrophils indicate that both GPR84 and FFA2R are involved in neutrophil recruitment processes in vivo. In summary, we show functional similarities but also some important differences between GPR84 and FFA2R in human phagocytes, thus providing some mechanistic insights into GPR84 regulation in blood neutrophils and cells recruited to an aseptic inflammatory site in vivo.
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| 38. |
- Welin, Amanda, 1983, et al.
(författare)
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CFP-10 from Mycobacterium tuberculosis Selectively Activates Human Neutrophils through a Pertussis Toxin-Sensitive Chemotactic Receptor.
- 2015
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Ingår i: Infection and immunity. - 1098-5522. ; 83:1, s. 205-213
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Tidskriftsartikel (refereegranskat)abstract
- Upon infection with Mycobacterium tuberculosis, neutrophils are massively recruited to the lungs, but the role of these cells in combating the infection is poorly understood. Through a type VII secretion system, M. tuberculosis releases a heterodimeric protein complex, containing a 6-kDa early secreted antigenic target (ESAT-6) and a 10-kDa culture filtrate protein (CFP-10), that is essential for virulence. Whereas the ESAT-6 component possesses multiple virulence-related activities, no direct biological activity of CFP-10 has been shown, and CFP-10 has been described as a chaperone protein for ESAT-6. We here show that the ESAT-6:CFP-10 complex induces a transient release of Ca(2+) from intracellular stores in human neutrophils. Surprisingly, CFP-10 rather than ESAT-6 was responsible for triggering the Ca(2+) response, in a pertussis toxin-sensitive manner, suggesting the involvement of a G-protein-coupled receptor. In line with this, the response was accompanied by neutrophil chemotaxis and activation of the superoxide-producing NADPH-oxidase. Neutrophils were unique among leukocytes in responding to CFP-10, as monocytes and lymphocytes failed to produce a Ca(2+) signal upon stimulation with the M. tuberculosis protein. Hence, CFP-10 may contribute specifically to neutrophil recruitment and activation during M. tuberculosis infection, representing a novel biological role for CFP-10 in the ESAT-6:CFP-10 complex, beyond the previously described chaperone function.
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| 39. |
- Welin, Amanda, 1983, et al.
(författare)
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The Human Neutrophil Subsets Defined by the Presence or Absence of OLFM4 Both Transmigrate into Tissue In Vivo and Give Rise to Distinct NETs In Vitro.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil heterogeneity was described decades ago, but it could not be elucidated at the time whether the existence of different neutrophil subsets had any biological relevance. It has been corroborated in recent years that neutrophil subsets, defined by differential expression of various markers, are indeed present in human blood, calling for renewed attention to this question. The expression of the granule protein olfactomedin 4 (OLFM4) has been suggested to define two such neutrophil subsets. We confirm the simultaneous presence of one OLFM4-positive and one OLFM4-negative neutrophil subpopulation as well as the localization of the protein to specific granules. In vitro, these neutrophil subsets displayed equal tendency to undergo apoptosis and phagocytose bacteria. In addition, the subpopulations were recruited equally to inflammatory sites in vivo, and this was true both in an experimental model of acute inflammation and in naturally occurring pathological joint inflammation. In line with its subcellular localization, only limited OLFM4 release was seen upon in vivo transmigration, and release through conventional degranulation required strong secretagogues. However, extracellular release of OLFM4 could be achieved upon formation of neutrophil extracellular traps (NETs) where it was detected only in a subset of the NETs. Although we were unable to demonstrate any functional differences between the OLFM4-defined subsets, our data show that different neutrophil subsets are present in inflamed tissue in vivo. Furthermore, we demonstrate NETs characterized by different markers for the first time, and our results open up for functions of OLFM4 itself in the extracellular space through exposure in NETs.
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| 40. |
- Önnheim, Karin, et al.
(författare)
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Tumour necrosis factor (TNF)-alpha primes murine neutrophils when triggered via formyl peptide receptor-related sequence 2, the murine orthologue of human formyl peptide receptor-like 1, through a process involving the type I TNF receptor and subcellular granule mobilization
- 2008
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Ingår i: Immunology. - : Wiley. - 1365-2567 .- 0019-2805. ; 125
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil granulocytes play an important role in innate host defence against microbial invasions and they are also the key effector cells in mediating host tissue damage. These functions often rely on the production of reactive oxygen species (ROS) from the membrane-bound NADPH-oxidase system. The magnitude of ROS production varies depending on the state of the cells, i.e. resting or primed. Many priming agents as well as potent NADPH-oxidase activators have been identified and characterized for human neutrophils. The cytokine tumour necrosis factor (TNF)-alpha is one prominent example of a priming agent and the synthetic hexapeptide WKYMVm is an agonist that triggers an activation of the NADPH-oxidase of human neutrophils through two members of the formyl peptide family of receptors, formyl peptide receptor (FPR) and FPR-like 1 (FPRL1). This peptide also activates murine neutrophils but the precise receptor involved has not been previously characterized. We show in this study that WKYMVm activates stably transfected HL60 cells expressing murine formyl peptide receptor-related sequence 2 (Fpr-rs2) and that activation of murine neutrophils with WKYMVm is blocked by an FPRL1-specific antagonist. WKYMVm is thus an agonist for Fpr-rs2 and we suggest that this receptor is in fact the mouse orthologue of FPRL1. In addition, we show that the WKYMVm response in murine neutrophils can be primed by TNF-alpha and this priming process involves mobilization of subcellular granules. The results obtained using neutrophils derived from TNF receptor type I (TNFRI)-deficient animals suggest that TNF-alpha exerts its priming effect via the TNFRI.
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