• MeSH
• aktivace neutrofilů imunologie   MeSH
• extracelulární pasti imunologie   MeSH
• imunitní systém imunologie   patologie   MeSH
• lidé MeSH
• neutrofily * imunologie   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Neutrophils play an important role as the central mediators of the innate immune defence response, providing the first line of host protection. It was shown that these cells can trap and kill various microorganisms through different ways. One of them is a release of neutrophil extracellular traps (NETs) composed of chromatin fibrils and antimicrobial proteins. There is the evidence that the release of NETs does not have only a beneficial effect. NETs can trap and kill microorganisms and pathogens, however on the other hand the same pathway can also cause the damage of the organism by various mechanisms. NETs participate in the pathogenesis of a lot of inflammatory and autoimmune disorders, such as thrombosis, atherosclerosis, cystic fibrosis, periodontitis, lupus, rheumatoid arthritis and others. The aim of this review is to summarize information about the release of NETs and their beneficial, but also detrimental effect during various diseases. The better characterization and understanding of the dual role of NETosis during these diseases is necessary for the early diagnosis and more effective treatment.

• MeSH
• apoptóza MeSH
• autoimunitní nemoci imunologie   metabolismus   patologie   MeSH
• cystická fibróza imunologie   metabolismus   patologie   MeSH
• extracelulární pasti imunologie   metabolismus   mikrobiologie   MeSH
• kardiovaskulární nemoci imunologie   metabolismus   patologie   MeSH
• neutrofily metabolismus   patologie   MeSH
• parodontitida imunologie   metabolismus   patologie   MeSH
• zánět imunologie   patofyziologie   patologie   MeSH

INTRODUCTION: Neutrophil extracellular traps (NETs) are formed by activated neutrophils during the process of NETosis in which the nuclear material is released into extracellular space, including DNA molecules, citrullinated histones, and neutrophil granule enzymes, such as elastase. This material forms networks that are able not only to physically entrap bacteria but also to provide elevated concentration of bactericidal components. Over the last years, it has become clear that NETs can also be formed under numerous sterile inflammatory conditions, i.e., thrombosis, cancer, SLE, atherosclerosis, and diabetes. METHOD: We reviewed studies published until July 2016 to find possible associations between elevated cell-free DNA levels in dialyzed patients and the process of NETosis and its consequences. RESULTS: The process of NETosis, its elevated activation, or impaired clearance provides the link between clinical conditions and elevated levels of cell-free DNA found in plasma after the hemodialytic procedure which itself is able to activate neutrophils via platelets and ROS formation. NETs stimulate thrombosis and endothelial damage, and their formation may contribute to the development of spectrum of comorbidities described in dialyzed patients. CONCLUSION: The study of plasma cell-free DNA levels together with markers of NETosis could contribute to the evaluation of the influence of hemodialysis on the immune system of patients.

• MeSH
• dialýza ledvin * MeSH
• extracelulární pasti * MeSH
• komorbidita MeSH
• lidé MeSH
• membrány umělé MeSH
• neutrofily MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

S100A11 (calgizzarin), a member of S100 family, is associated with several autoimmune diseases, including rheumatoid arthritis (RA). Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of RA and in the externalization of some S100 family members. Therefore, we aimed to determine the association between S100A11 and NETs in RA. For this purpose, the levels of S100A11 and NETosis markers were detected in the RA synovial fluid by immunoassays. The expression of S100A11 by neutrophils in the RA synovial tissue was assessed. Neutrophils isolated from peripheral blood were exposed to S100A11 or stimulated to release NETs. The levels of NETosis- and inflammation-associated proteins were analysed by immunoassays. NETs were visualized by immunofluorescence. We showed that S100A11 was expressed by the neutrophils in the RA synovial tissue. Moreover, S100A11 in the RA synovial fluid correlated with several NETosis markers. In vitro, S100A11 was abundantly released by neutrophils undergoing NETosis compared to untreated cells (p < 0.001). Extracellular S100A11 increased the secretion of IL-6 (p < 0.05) and TNF (p < 0.05) by neutrophils but did not induce NETosis. This study demonstrates, for the first time, that the release of S100A11 is dependent on NETosis and that extracellular S100A11 augments the inflammatory response by inducing pro-inflammatory cytokines in neutrophils.

• MeSH
• dospělí MeSH
• extracelulární pasti metabolismus   MeSH
• interleukin-6 metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neutrofily metabolismus   patologie   MeSH
• proteiny S100 metabolismus   MeSH
• revmatoidní artritida metabolismus   patologie   MeSH
• senioři MeSH
• synoviální tekutina metabolismus   MeSH
• TNF-alfa metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH

Type 1 diabetes (T1D) is an autoimmune disorder with unambiguous involvement of both innate and adaptive immune mechanisms in the destruction of pancreatic beta cells. Recent evidence demonstrated that neutrophils infiltrate the pancreas prior to disease onset and therein extrude neutrophil extracellular traps (NETs), web-like structures of DNA and nuclear proteins with a strong pro-inflammatory biologic activity. Our previous work showed that T1D NETs activate dendritic cells, which consequently induce IFNγ-producing Th1 lymphocytes. The aim of this study was to assess direct ex vivo biomarkers of NETosis in the serum of recent onset and long-term pediatric T1D patients, their first-degree relatives and healthy controls. To this end we evaluated serum levels of myeloperoxidase (MPO), neutrophil elastase (NE), proteinase 3 (PR3), protein arginine deiminase 4 (PAD4), LL37 and cell-free DNA-histone complexes in sex- and age-matched cohorts of T1D first-degree relatives, recent-onset T1D patients, and in patients 12 months after clinical manifestation of the disease. Our data shows that disease onset is accompanied by peripheral neutrophilia and significant elevation of MPO, NE, PR3, PAD4 and cell-free DNA-histone complexes. Most biomarkers subsequently decrease but do not always normalize in long-term patients. First-degree relatives displayed an intermediate phenotype, except for remarkably high levels of LL37. Together, this report provides evidence for the presence of ongoing NETosis in pediatric patients with T1D at time of clinical manifestation of the disease, which partly subsides in subsequent years.

• MeSH
• biologické markery krev   MeSH
• diabetes mellitus 1. typu krev   imunologie   MeSH
• dítě MeSH
• dospělí MeSH
• extracelulární pasti * MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neutrofily imunologie   MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Background: Interleukin 40 (IL-40) is a newly identified B cell-associated cytokine implicated in humoral immune responses and B cell homeostasis. As B cells play a pivotal role in autoimmunity, we investigated the function of IL-40 in rheumatoid arthritis (RA). Methods: IL-40 expression was determined in the synovial tissue from RA and osteoarthritis (OA) patients. IL-40 was analysed in the serum/synovial fluid of patients with RA (n=50), systemic lupus erythematosus (SLE, n=69), OA (n=44), and healthy controls (HC, n=50). We assessed the changes of IL-40 levels in RA patients following the B cell depletion by rituximab (n=29) or after the TNF inhibition by adalimumab (n=25). We examined the relationship between IL-40, disease activity, autoantibodies, cytokines, and NETosis markers. Effect of IL-40 on synovial fibroblasts was determined. Results: IL-40 was overexpressed in RA synovial tissue, particularly by synovial lining and infiltrating immune cells. The levels of IL-40 were up-regulated in the synovial fluid of RA versus OA patients (p<0.0001). Similarly, IL-40 was increased in the serum of RA patients compared to HC, OA, or SLE (p<0.0001 for all) and decreased after 16 and 24 weeks (p<0.01 and p<0.01) following rituximab treatment. No significant effect of adalimumab on IL-40 was observed. IL-40 levels in RA patients correlated with rheumatoid factor-IgM and anti-cyclic citrullinated peptides (anti-CCP) in the serum (p<0.0001 and p<0.01), as well as in the synovial fluid (p<0.0001 and p<0.001). Synovial fluid IL-40 was also associated with disease activity score DAS28 (p<0.05), synovial fluid leukocyte count (p<0.01), neutrophil attractants IL-8 (p<0.01), MIP-1α (p<0.01), and markers of neutrophil extracellular traps externalization (NETosis) such as proteinase 3 (p<0.0001) and neutrophil elastase (p<0.0001). Synovial fibroblasts exposed to IL-40 increased the secretion of IL-8 (p<0.01), MCP-1 (p<0.05), and MMP-13 (p<0.01) compared to the unstimulated cells. Conclusions: We show the up-regulation of IL-40 in RA and its decrease following B cell depleting therapy. The association of IL-40 with autoantibodies, chemokines, and markers of NETosis may imply its potential involvement in RA development. Moreover, IL-40 up-regulates the secretion of chemokines and MMP-13 in synovial fibroblasts, indicating its role in the regulation of inflammation and tissue destruction in RA.

• MeSH
• adalimumab terapeutické užití   MeSH
• artróza kolenních kloubů imunologie   metabolismus   MeSH
• autoprotilátky krev   MeSH
• B-lymfocyty účinky léků   imunologie   MeSH
• biologické markery MeSH
• cytokiny analýza   MeSH
• dospělí MeSH
• extracelulární pasti imunologie   MeSH
• fibroblasty MeSH
• kohortové studie MeSH
• kultivované buňky MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfocytární deplece MeSH
• matrixová metaloproteinasa 13 analýza   MeSH
• regulace genové exprese účinky léků   MeSH
• revmatoidní artritida genetika   imunologie   metabolismus   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• senioři MeSH
• synoviální membrána chemie   imunologie   MeSH
• synoviální tekutina chemie   imunologie   MeSH
• systémový lupus erythematodes imunologie   metabolismus   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: Interleukin (IL)-40 is a new cytokine related to immune system function and malignancies. Recently, an association of IL-40 with rheumatoid arthritis (RA) and externalisation of neutrophil extracellular traps (NETosis) was found. As neutrophils are implicated in RA development, we investigated IL-40 in early stages of RA (ERA). METHODS: IL-40 was determined in serum of treatment naïve patients with ERA at baseline (n=60) and 3 months after initiation of conventional therapy and in healthy controls (HC; n=60). Levels of IL-40, cytokines and NETosis markers were measured by ELISA. NETosis was visualised by immunofluorescence. In vitro experiments were performed on peripheral blood neutrophils from ERA patients (n=14). Cell-free DNA was analysed in serum and supernatants. RESULTS: Serum IL-40 was elevated in ERA compared with HC (p<0.0001) and normalised after 3 months of therapy (p<0.0001). Baseline serum IL-40 correlated with rheumatoid factor (IgM) (p<0.01), anti-cyclic citrullinated peptide (p<0.01) autoantibodies and NETosis markers (proteinase 3; neutrophil elastase (NE); myeloperoxidase) (p<0.0001). Levels of NE significantly decreased after therapy (p<0.01) and correlated with the decrease of serum IL-40 (p<0.05). In vitro, neutrophils enhanced IL-40 secretion following NETosis induction (p<0.001) or after exposure to IL-1β, IL-8 (p<0.05), tumour necrosis factor or lipopolysaccharide (p<0.01). Recombinant IL-40 up-regulated IL-1β, IL-6 and IL-8 (p<0.05 for all) in vitro. CONCLUSION: We showed that IL-40 is significantly up-regulated in seropositive ERA and decreases after conventional therapy. Moreover, neutrophils are an important source of IL-40 in RA, and its release is potentiated by cytokines and NETosis. Thus, IL-40 may play a role in ERA.

• MeSH
• autoprotilátky MeSH
• cytokiny MeSH
• interleukin-8 MeSH
• interleukiny MeSH
• lidé MeSH
• neutrofily * MeSH
• revmatoidní artritida * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Diabetes is associated with dire peripheral sequelae including foot ulcers and amputations. A recent article by Wong et al. demystifies this connection by demonstrating that the neutrophil defense mechanism of extruding decondensed chromatin, termed NETosis, mediates delayed wound healing in diabetes and provides a therapeutic strategy for this indication.

• MeSH
• citrulin metabolismus   MeSH
• extracelulární pasti * účinky léků   MeSH
• hojení ran * účinky léků   MeSH
• hydrolasy genetika   metabolismus   MeSH
• komplikace diabetu patologie   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Circulating extracellular DNA (ecDNA) is known to worsen the outcome of many diseases. ecDNA released from neutrophils during infection or inflammation is present in the form of neutrophil extracellular traps (NETs). It has been shown that higher ecDNA concentration occurs in a number of inflammatory diseases including inflammatory bowel disease (IBD). Enzymes such as peptidyl arginine deiminases (PADs) are crucial for NET formation. We sought to describe the dynamics of ecDNA concentrations and fragmentation, along with NETosis during a mouse model of chemically induced colitis. Plasma ecDNA concentration was highest on day seven of dextran sulfate sodium (DSS) intake and the increase was time-dependent. This increase correlated with the percentage of cells undergoing NETosis and other markers of disease activity. Relative proportion of nuclear ecDNA increased towards more severe colitis; however, absolute amount decreased. In colon explant medium, the highest concentration of ecDNA was on day three of DSS consumption. Early administration of PAD4 inhibitors did not alleviate disease activity, but lowered the ecDNA concentration. These results uncover the biological characteristics of ecDNA in IBD and support the role of ecDNA in intestinal inflammation. The therapeutic intervention aimed at NETs and/or nuclear ecDNA has yet to be fully investigated.

• MeSH
• biologické markery metabolismus   MeSH
• deoxyribonukleasy metabolismus   MeSH
• DNA krev   metabolismus   MeSH
• endoskopie MeSH
• extracelulární pasti účinky léků   metabolismus   MeSH
• extracelulární prostor metabolismus   MeSH
• kolitida krev   chemicky indukované   patologie   MeSH
• mitochondriální DNA krev   MeSH
• myši inbrední C57BL MeSH
• ornithin analogy a deriváty   farmakologie   MeSH
• peptidylarginindeiminasa typu 4 metabolismus   MeSH
• síran dextranu MeSH
• streptonigrin farmakologie   MeSH
• střeva účinky léků   patologie   MeSH
• střevní sliznice účinky léků   patologie   MeSH
• stupeň závažnosti nemoci MeSH
• zánět krev   patologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Objective: Posttranslational modifications (PTMs) of proteins are crucial for regulating various biological processes. However, protein alteration via PTMs, and consequently, the creation of new epitopes, can induce abnormal autoimmune responses in predisposed individuals. Immunopathogenesis of several rheumatic diseases, including the most common childhood form, juvenile idiopathic arthritis (JIA), is associated with the generation of autoantibodies against such modified proteins. Dysregulated generation of neutrophil extracellular traps (NETs) can be a source of post-translationally altered proteins. Thus, we investigated the role of PTMs and the presence of NET-associated markers in JIA patients. Methods: We recruited 30 pediatric patients with JIA (20 with active disease and 10 in remission) and 30 healthy donors. The serum concentrations of citrullinated histone H3 (citH3), peptidyl arginine deiminases (PADs), and NET-related products were detected using ELISA, and the number of citH3+ neutrophils was assessed using flow cytometry. Results: The serum levels of citH3 and PADs were higher in active as well as in remission JIA patients than in healthy donors. Similarly, the number of citH3+ neutrophils was higher in the peripheral blood of patients with JIA, implying an enhanced process of NETosis. This was effectively reflected by elevated serum levels of NET-associated products, such as neutrophil elastase, LL37, and cell-free DNA-histone complexes. Additionally, 16.7% of active JIA patients were seropositive for carbamylated autoantibodies, the levels of which declined sharply after initiation of anti-TNFα therapy. Conclusion: Collectively, our data suggest that the accelerated process of NETosis and PTMs in JIA may result in the generation of anti-citrullinated/carbamylated autoantibodies against various epitopes later in life, which could be prevented by effectively regulating inflammation using immune therapy.

• Publikační typ
• časopisecké články MeSH