1.
Egesten, Arne, et al.
(författare)
SpeB of Streptococcus pyogenes differentially modulates antibacterial and receptor activating properties of human chemokines.
2009
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:3
Tidskriftsartikel (refereegranskat) abstract
BACKGROUND: CXC chemokines are induced by inflammatory stimuli in epithelial cells and some, like MIG/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, are antibacterial for Streptococcus pyogenes. METHODOLOGY/PRINCIPAL FINDINGS: SpeB from S. pyogenes degrades a wide range of chemokines (i.e. IP10/CXCL10, I-TAC/CXCL11, PF4/CXCL4, GROalpha/CXCL1, GRObeta/CXCL2, GROgamma/CXCL3, ENA78/CXCL5, GCP-2/CXCL6, NAP-2/CXCL7, SDF-1/CXCL12, BCA-1/CXCL13, BRAK/CXCL14, SRPSOX/CXCL16, MIP-3alpha/CCL20, Lymphotactin/XCL1, and Fractalkine/CX3CL1), has no activity on IL-8/CXCL8 and RANTES/CCL5, partly degrades SRPSOX/CXCL16 and MIP-3alpha/CCL20, and releases a 6 kDa CXCL9 fragment. CXCL10 and CXCL11 loose receptor activating and antibacterial activities, while the CXCL9 fragment does not activate the receptor CXCR3 but retains its antibacterial activity. CONCLUSIONS/SIGNIFICANCE: SpeB destroys most of the signaling and antibacterial properties of chemokines expressed by an inflamed epithelium. The exception is CXCL9 that preserves its antibacterial activity after hydrolysis, emphasizing its role as a major antimicrobial on inflamed epithelium.
2.
Kasetty, Gopinath, et al.
(författare)
Osteopontin protects against lung injury caused by extracellular histones
2019
Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219 .- 1935-3456. ; 12:1, s. 39-50
Tidskriftsartikel (refereegranskat) abstract
Extracellular histones are present in the airways because of cell death occurring during inflammation. They promote inflammation and cause tissue damage due to their cationic nature. The anionic phosphoglycoprotein osteopontin (OPN) is expressed at high levels during airway inflammation and has been ascribed both pro- and anti-inflammatory roles. In this study, it was hypothesized that OPN may neutralize the harmful activities of extracellular histones at the airway mucosal surface. In a model of histone-induced acute lung injury, OPN−/− mice showed increased inflammation and tissue injury, and succumbed within 24 h, whereas wild-type mice showed lower degrees of inflammation and no mortality. In lipopolysaccharide-induced acute lung injury, wild-type mice showed less inflammation and tissue injury than OPN−/− mice. In bronchoalveolar lavage fluid from ARDS patients, high levels of OPN and also histone–OPN complexes were detected. In addition, OPN bound to histones with high affinity in vitro, resulting in less cytotoxicity and reduced formation of tissue-damaging neutrophil extracellular traps (NETs). The interaction between OPN and histones was dependent on posttranslational modification of OPN, i.e., phosphorylation. The findings demonstrate a novel role for OPN, modulating the pro-inflammatory and cytotoxic properties of free histones.
3.
Bergwik, Jesper, et al.
(författare)
Macrophage expressed tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis progression
2024
Ingår i: Immunology. - 0019-2805. ; 171:4, s. 583-594
Tidskriftsartikel (refereegranskat) abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder involving scarring of pulmonary tissue and a subsequent decrease in respiratory capacity, ultimately resulting in death. Tartrate resistant acid phosphatase 5 (ACP5) plays a role in IPF but the exact mechanisms are yet to be elucidated. In this study, we have utilized various perturbations of the bleomycin mouse model of IPF including genetic knockout, RANKL inhibition, and macrophage adoptive transfer to further understand ACP5's role in pulmonary fibrosis. Genetic ablation of Acp5 decreased immune cell recruitment to the lungs and reduced the levels of hydroxyproline (reflecting extracellular matrix-production) as well as histological damage. Additionally, gene expression profiling of murine lung tissue revealed downregulation of genes including Ccl13, Mmp13, and Il-1α that encodes proteins specifically related to immune cell recruitment and macrophage/fibroblast interactions. Furthermore, antibody-based neutralization of RANKL, an important inducer of Acp5 expression, reduced immune cell recruitment but did not decrease fibrotic lung development. Adoptive transfer of Acp5 -/- bone marrow-derived monocyte (BMDM) macrophages 7 or 14 days after bleomycin administration resulted in reductions of cytokine production and decreased levels of lung damage, compared to adoptive transfer of WT control macrophages. Taken together, the data presented in this study suggest that macrophage derived ACP5 plays an important role in development of pulmonary fibrosis and could present a tractable target for therapeutic intervention in IPF.
4.
Alvarado-Vazquez, P. Abigail
(författare)
Mast cells and their progenitors in respiratory diseases : Understanding their connection to lung function and airway inflammation
2023
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Mast cells are rare immune cells involved in allergic diseases, including asthma. These cells are derived from mast cell progenitors (MCps) that migrate to the peripheral tissues via the blood in response to allergic or non-allergic stimuli. The main purpose of this thesis was to investigate the role of mast cells and MCps in the lung function decline observed in mouse models of airway inflammation. We also investigated the MCp frequency during natural allergen exposure using patient samples. Our aim in paper I was to investigate the effect of age and weight on lung function parameters in naïve mice using a pulmonary function test (PFT). We showed that age and weight positively correlated with lung function and successfully used the PFT to monitor asthma outcomes and distinguish between treated and untreated experimental asthma.In paper II, we investigated the specificity of a basophil-deficient mouse model that relies on the deletion of the mast cell protease 8 (mMCP-8), a classical basophil marker. We found that lung mast cells expressed mMCP-8, and deleting this protease reduced lung mast cells in mice with allergic airway inflammation.Mast cells express ST2 and thus can be activated by interleukin-33 (IL-33). Hence, in paper III, we used Cpa3cre/+ mast cell-deficient mice to investigate the role of mast cells in airway inflammation induced by intranasal IL-33 administration. We identified a new mechanism in which mast cells participate in T-cells mobilization into the alveolar space via the CXCL1/CXCR2 axis. We have previously described increased circulating MCps in subjects with reduced lung function. However, if and how MCps change upon allergen exposure is unknown. Therefore, in paper IV, we investigated the frequency of blood MCps in birch pollen-sensitized asthma patients in and out of the birch pollen season. We demonstrated that in allergic asthma patients, circulating MCps were increased during natural pollen exposure and were associated with more asthma symptoms and less asthma control.This thesis involves both basic and translational research and provides new insights into the role of mast cells and their progenitors in type 2 inflammation.
5.
Papareddy, Praveen, et al.
(författare)
An ecoimmunological approach to study evolutionary and ancient links between coagulation, complement and Innate immunity
2018
Ingår i: Virulence. - : Informa UK Limited. - 2150-5608 .- 2150-5594. ; 9:1, s. 724-737
Tidskriftsartikel (refereegranskat) abstract
Coagulation, complement, and innate immunity are tightly interwoven and form an alliance that can be traced back to early eukaryotic evolution. Here we employed an ecoimmunological approach using Tissue Factor Pathway Inhibitor (TFPI)-1-derived peptides from the different classes of vertebrates (i.e. fish, reptile, bird, and mammals) and tested whether they can boost killing of various human bacterial pathogens in plasma. We found signs of species-specific conservation and diversification during evolution in these peptides that significantly impact their antibacterial activity. Though all peptides tested executed bactericidal activity in mammalian plasma (with the exception of rodents), no killing was observed in plasma from birds, reptiles, and fish, pointing to a crucial role for the classical pathway of the complement system. We also observed an interference of these peptides with the human intrinsic pathway of coagulation though, unlike complement activation, this mechanism appears not to be evolutionary conserved.
6.
7.
Tanner, Lloyd, et al.
(författare)
Tartrate resistant acid phosphatase 5 (TRAP5) mediates immune cell recruitment in a murine model of pulmonary bacterial infection
2022
Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
Tidskriftsartikel (refereegranskat) abstract
Introduction: During airway infection, upregulation of proinflammatory cytokines and subsequent immune cell recruitment is essential to mitigate bacterial infection. Conversely, during prolonged and non-resolving airway inflammation, neutrophils contribute to tissue damage and remodeling. This occurs during diseases including cystic fibrosis (CF) and COPD where bacterial pathogens, not least Pseudomonas aeruginosa, contribute to disease progression through long-lasting infections. Tartrate-resistant acid phosphatase (TRAP) 5 is a metalloenzyme expressed by alveolar macrophages and one of its target substrates is the phosphoglycoprotein osteopontin (OPN).Methods: We used a knockout mouse strain (Trap5-/-) and BALB/c-Tg (Rela-luc)31Xen mice paired with siRNA administration or functional protein add-back to elucidate the role of Trap5 during bacterial infection. In a series of experiments, Trap5-/- and wild-type control mice received intratracheal administration of P.aerugniosa (Xen41) or LPS, with mice monitored using intravital imaging (IVIS). In addition, multiplex cytokine immunoassays, flow cytometry, multispectral analyses, histological staining were performed.Results: In this study, we found that Trap5-/- mice had impaired clearance of P. aeruginosa airway infection and reduced recruitment of immune cells (i.e. neutrophils and inflammatory macrophages). Trap5 knockdown using siRNA resulted in a decreased activation of the proinflammatory transcription factor NF-κB in reporter mice and a subsequent decrease of proinflammatory gene expression. Add-back experiments of enzymatically active TRAP5 to Trap5-/- mice restored immune cell recruitment and bacterial killing. In human CF lung tissue, TRAP5 of alveolar macrophages was detected in proximity to OPN to a higher degree than in normal lung tissue, indicating possible interactions.Discussion: Taken together, the findings of this study suggest a key role for TRAP5 in modulating airway inflammation. This could have bearing in diseases such as CF and COPD where excessive neutrophilic inflammation could be targeted by pharmacological inhibitors of TRAP5.
8.
9.
Egesten, Arne, et al.
(författare)
A Leak in the Dike
2020
Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 12:5, s. 355-356
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
10.
Egesten, Arne, et al.
(författare)
Going Fishing
2018
Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 10:1, s. 1-2
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
