| 1. |
- Abdulla, Aree, et al.
(författare)
-
Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis.
- 2011
-
Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 90, s. 975-982
-
Tidskriftsartikel (refereegranskat)abstract
- The relationship between inflammation and proteolytic activation in pancreatitis is an unresolved issue in pancreatology. The purpose of this study was to define the influence of neutrophils on trypsinogen activation in severe AP. Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. For neutrophil depletion, an anti-Gr-1 antibody was administered before pancreatitis induction. Administration of the anti-Gr-1 antibody reduced circulating neutrophils by 97%. Pancreatic TAP and serum amylase levels increased 2 h and 24 h after induction of pancreatitis. Neutrophil depletion reduced pancreatic TAP and serum amylase levels at 24 h but not at 2 h after pancreatitis induction. Pancreatic MPO and infiltration of neutrophils, as well as MIP-2 levels, were increased 24 h after taurocholate infusion. Two hours after taurocholate administration, no significant pancreatic infiltration of neutrophils was observed. Injection of the anti-Gr-1 antibody abolished MPO activity, neutrophil accumulation, and MIP-2 levels, as well as acinar cell necrosis, hemorrhage, and edema in the pancreas at 24 h. Moreover, taurocholate-provoked tissue damage and MPO activity in the lung were normalized by neutrophil depletion. Intravital fluorescence microscopy revealed a 97% reduction of leukocytes in the pancreatic microcirculation after administration of the anti-Gr-1 antibody. Our data demonstrate that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils in the pancreas. Neutrophils are critical in mediating pancreatic and lung tissue damage in severe AP.
|
|
| 2. |
- Amirbeagi, Firoozeh, et al.
(författare)
-
Olfactomedin-4 autoantibodies give unusual c-ANCA staining patterns with reactivity to a subpopulation of neutrophils.
- 2015
-
Ingår i: Journal of leukocyte biology. - 1938-3673. ; 97:1, s. 181-189
-
Tidskriftsartikel (refereegranskat)abstract
- Testing for the presence of ANCAs in circulation is part of the clinical examinations routinely performed upon suspected autoimmune disorders, mainly vasculitis. The autoantibodies are typically directed toward neutrophil MPO or PR3. These are major granule-localized proteins, and similar to all hitherto-described ANCA antigens, they are expressed by all neutrophils, and ANCA-containing sera thus give rise to uniform reactivity toward all neutrophils in a sample. In this paper, we describe sera from 2 unrelated patients with diffuse inflammatory symptoms that gave rise to peculiar c-ANCA patterns, only reacting with a subpopulation (roughly 30%) of human neutrophils. By immunoblotting, both sera reacted to the same antigen, which was expressed in intracellular granules. The antigen could be released to the extracellular milieu through secretion but also through the formation of NETs. Neutrophils have long been considered a homogenous cell population, but it is becoming increasingly clear that distinct subpopulations, defined by the presence or absence of certain proteins, exist. One such marker that defines a neutrophil subset is the granule protein OLFM4. The unusual, subset-restricted c-ANCA sera reacted only with OLFM4-positive neutrophils, and MS analysis revealed that the autoantigen was, in fact, OLFM4. These data describe for the first time a c-ANCA pattern reactive to only a subpopulation of neutrophils and identify the granule protein OLFM4 as a novel autoantigen.
|
|
| 3. |
- Andersson, A, et al.
(författare)
-
Differential macrophage expression of IL-12 and IL-23 upon innate immune activation defines rat autoimmune susceptibility
- 2004
-
Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 76:6, s. 1118-1124
-
Tidskriftsartikel (refereegranskat)abstract
- Rodents typically demonstrate strain-specific susceptibilities to induced autoimmune models such as experimental arthritis and encephalomyelitis. A common feature of the local pathology of these diseases is an extensive infiltration of activated macrophages (MΦ). Different functional activation states can be induced in MΦ during innate immune activation, and it is this differential activation that might be important in susceptibility/resistance to induction or perpetuation of autoimmunity. In this study, we present an extensive, comparative analysis of the activation phenotypes of MΦ derived from autoimmune-susceptible and autoimmune-resistant rat strains to describe a cellular phenotype that defines the disease phenotype. We included investigation of receptor function, intracellular signaling pathways, cytokines, and other soluble mediators released after activation of cells using a panel of stimuli embracing many activation routes. We report that activation of MΦ from the autoimmune-susceptible strain was associated with alternative activation indicated by induction of arginase activity, a lower production of classical proinflammatory mediators, and a high production of interleukin (IL)-23, and MΦ from the autoimmune-resistant strains were associated with a higher production of proinflammatory mediators, a classical activation phenotype, and preferential induction of IL-12. These MΦ phenotypes thus reflect disparate, genetic cellular programs that define autoimmune susceptibility.
|
|
| 4. |
- Andersson, Karin, 1972, et al.
(författare)
-
Down-regulation of survivin alleviates experimental arthritis.
- 2015
-
Ingår i: Journal of leukocyte biology. - 1938-3673. ; 97:1, s. 135-45
-
Tidskriftsartikel (refereegranskat)abstract
- Survivin is a proto-oncogene that regulates cell division and apoptosis. It is a molecular marker of cancer. Recently, survivin has emerged as a feature of RA, associated with severe joint damage and poor treatment response. The present study examined if inhibition of survivin affects experimental arthritis, which was induced in mBSA-immunized mice by an injection of mBSA in the knee joint or developed spontaneously in collagen type II-immunized mice. The inhibition of survivin transcription by a lentivirus shRNA construct alleviated joint inflammation and reduced bone damage. The inhibition of survivin reduced the levels of metalloproteinases, β-catenin, and vimentin, limiting the invasive capacity of synovia, while no inhibition of osteoclastogenesis could be found. The inhibition of survivin led to a p53-independent reduction of T cell proliferation and favored the transcription and activity of Blimp-1, which limited IL-2 production and facilitated formation of regulatory Foxp3(+)CD4(+) and effector CD8(+) T cells. The study shows that the inhibition of survivin is sufficient to reduce joint inflammation and bone damage in preclinical models of arthritis. Antiarthritic effects of survivin inhibition are related to p53-independent control of lymphocyte proliferation.
|
|
| 5. |
- Andersson, Åsa, et al.
(författare)
-
Pivotal Advance : HMGB1 expression in active lesions of human and experimental multiple sclerosis
- 2008
-
Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 84:5, s. 1248-1255
-
Forskningsöversikt (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.
|
|
| 6. |
- Asplund, Annika, 1979, et al.
(författare)
-
Hypoxia increases macrophage motility, possibly by decreasing the heparan sulfate proteoglycan biosynthesis.
- 2009
-
Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 86:2, s. 381-8
-
Tidskriftsartikel (refereegranskat)abstract
- Macrophages are recruited and retained in hypoxic sites in atherosclerotic lesions and tumors. Furthermore, macrophages are suggested to be a major source of HSPG synthesis in atherosclerotic lesions. HSPG are, among other things, known to regulate cell motility, cell adhesion, and receptor interaction. The aim of this study was to investigate the effect of hypoxia on HSPG expression and macrophage motility. We also explored the potential regulation of HSPG by the transcription factor HIF-1alpha. The nondirected cell motility was increased in HMDM after 24 h exposure to hypoxia (0.5% O(2)) compared with normal cell culture condition (21% O(2)). Enzymatic degradation of HS GAG further increased the motility of the HMDM in hypoxia, indicating a role of reduced cell-associated HSPG in the increased HMDM motility. HMDM exposed to 24 h of hypoxia had lower mRNA expressions of syndecan-1 and -4 compared with cells exposed to normal cell culture conditions. Protein levels of syndecan-1 were also decreased significantly in response to hypoxia, and cells subjected to hypoxia had lower mRNA expression for key enzymes involved in HS biosynthesis. In addition, hypoxia was found to reduce the relative content of HS GAG. Transfecting THP-1 cells with siHIF-1alpha indicated that this transcription factor was not involved in the hypoxia-induced modifications of HSPG expression. Given the documented multiple functions of HSPG in macrophage behavior, the hypoxia-induced modifications of HSPG may be of relevance for the development of atherosclerotic lesions and tumor progression.
|
|
| 7. |
- Aurelius, Johan, 1980, et al.
(författare)
-
Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent inactivation and cell death in lymphocytes.
- 2013
-
Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 93:1, s. 155-160
-
Tidskriftsartikel (refereegranskat)abstract
- NK cells and T cells are commonly dysfunctional in CML, and their status may determine the course of disease. We aimed to define the molecular mechanisms of leukemia-induced immunosuppression with focus on the role of ROS and the PARP-1 pathway of cell death. Malignant granulocytes from patients with BCR-ABL-positive CML expressed the oxygen radical-producing enzyme NOX, produced large amounts of ROS, and triggered extensive cell death in NK cells. Inhibition of PARP-1 maintained NK cell viability in cocultures with suppressive leukemic cells. Under conditions of oxidative stress, PARP-1 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells, in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells. Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML.
|
|
| 8. |
- Aurelius, Johan, 1980, et al.
(författare)
-
NOX2-dependent immunosuppression in chronic myelomonocytic leukemia
- 2017
-
Ingår i: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 102:2, s. 459-466
-
Tidskriftsartikel (refereegranskat)abstract
- Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8(+) T effector memory cells, and CD8(+) T effector cells. Inhibitors of ROS formation and scavengers of extracellular ROS prevented CMML cell-induced lymphocyte death and facilitated NK cell degranulation toward Ab-coated, primary CMML cells. In patients with CMML, elevation of immature cell counts (CD34(+)) in blood was associated with reduced expression of several NK cell-activating receptors. We propose that CMML cells may use extracellular ROS as a targetable mechanism of immune escape.
|
|
| 9. |
- Awla, Darbaz, et al.
(författare)
-
Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis.
- 2012
-
Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 91, s. 711-719
-
Tidskriftsartikel (refereegranskat)abstract
- MMPs are generally considered to regulate degradation and remodeling of the ECM. Convincing data also implicate a role for MMPs in inflammatory conditions, such as AP, although the mechanisms are not known. The aim of this study was to define the role of MMPs in regulating activation of trypsinogen and tissue damage in AP, which was induced by infusion of taurocholate into the pancreatic duct in mice. A broad-spectrum MMP inhibitor (BB-94) and MMP-9 gene-deficient mice were used. Neutrophil secretions and rMMP-9 were used to stimulate trypsinogen activation in isolated acinar cells. Taurocholate challenge increased serum amylase, neutrophil infiltration, MIP-2 (CXCL2) formation, trypsinogen activation, and tissue damage in the pancreas. Treatment with the broad-spectrum inhibitor of MMPs, BB-94, markedly reduced activation of trypsinogen, levels of CXCL2, infiltration of neutrophils, and tissue damage in AP. Taurocholate challenge increased serum levels of MMP-9 but not MMP-2. Taurocholate-induced amylase levels, neutrophil accumulation, production of CXCL2, trypsinogen activation, and tissue damage in the pancreas were abolished in MMP-9-deficient mice. Moreover, secretions from activated neutrophils isolated from WT but not from MMP-9-deficient animals stimulated trypsinogen activation in acinar cells. Notably, rMMP-9 greatly enhanced activation of trypsinogen in acinar cells. These findings demonstrate that neutrophil-derived MMP-9 is a potent activator of trypsinogen in acinar cells and regulates pathological inflammation and tissue damage in AP.
|
|
| 10. |
- Barratt-Due, Andreas, et al.
(författare)
-
Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases-C3 or C5 emerge together with CD14 as promising targets.
- 2017
-
Ingår i: Journal of Leukocyte Biology. - 0741-5400 .- 1938-3673. ; 101:1, s. 193-204
-
Tidskriftsartikel (refereegranskat)abstract
- The host is protected by pattern recognition systems, including complement and TLRs, which are closely cross-talking. If improperly activated, these systems might induce tissue damage and disease. Inhibition of single downstream proinflammatory cytokines, such as TNF, IL-1β, and IL-6, have failed in clinical sepsis trials, which might not be unexpected, given the substantial amounts of mediators involved in the pathogenesis of this condition. Instead, we have put forward a hypothesis of inhibition at the recognition phase by "dual blockade" of bottleneck molecules of complement and TLRs. By acting upstream and broadly, the dual blockade could be beneficial in conditions with improper or uncontrolled innate immune activation threatening the host. Key bottleneck molecules in these systems that could be targets for inhibition are the central complement molecules C3 and C5 and the important CD14 molecule, which is a coreceptor for several TLRs, including TLR4 and TLR2. This review summarizes current knowledge of inhibition of complement and TLRs alone and in combination, in both sterile and nonsterile inflammatory processes, where activation of these systems is of crucial importance for tissue damage and disease. Thus, dual blockade might provide a general, broad-acting therapeutic regimen against a number of diseases where innate immunity is improperly activated.
|
|
