scholarly journals Neutrophil-mediated carbamylation promotes articular damage in rheumatoid arthritis

2020 ◽  
Vol 6 (44) ◽  
pp. eabd2688 ◽  
Author(s):  
Liam J. O’Neil ◽  
Ana Barrera-Vargas ◽  
Donavon Sandoval-Heglund ◽  
Javier Merayo-Chalico ◽  
Eduardo Aguirre-Aguilar ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Responses ◽  
Shared Epitope ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Neutrophil Extracellular Traps ◽  
Erosive Arthritis ◽  
Extracellular Traps ◽  
Articular Damage

Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti–carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti–carbamylated histone–immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.

scholarly journals Propionibacterium freudenreichii Inhibits RANKL-Induced Osteoclast Differentiation and Ameliorates Rheumatoid Arthritis in Collagen-Induced Arthritis Mice

2021 ◽  
Vol 10 (1) ◽  
pp. 48
Author(s):  
Jiah Yeom ◽  
Dong Joon Yim ◽  
Seongho Ma ◽  
Young-Hee Lim
Keyword(s):  
Rheumatoid Arthritis ◽  
Mouse Model ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Joint Damage ◽  
Bone Destruction ◽  
In Vivo Studies ◽  
Propionibacterium Freudenreichii ◽  
Limited Information ◽  
Collagen Induced Arthritis

Osteoclast differentiation is crucial for bone absorption, and osteoclasts are involved in bone destruction in rheumatoid arthritis (RA). Dairy Propionibacterium freudenreichii is used as a cheese starter and possesses prebiotic and postbiotic properties. It is known to stimulate the growth of bifidobacteria and produces valuable metabolites, such as vitamin B12 and propionic acid. However, limited information is available on the beneficial effects of P. freudenreichii on human disease. Herein, we aimed to investigate the inhibitory effect of P. freudenreichii MJ2 (MJ2) isolated from raw milk on osteoclast differentiation and evaluate the improvement in RA. The murine macrophage cell line, RAW 264.7, and a collagen-induced arthritis (CIA) mouse model were used to perform in vitro and in vivo studies, respectively. Heat-killed P. freudenreichii MJ2 (hkMJ2)-treated cells significantly inhibited RANKL-induced osteoclast differentiation and TRAP activity. HkMJ2-treated cells exhibited significantly decreased expression of genes and proteins related to RANKL-induced osteoclast differentiation. MJ2 administration decreased the arthritic score in the CIA mouse model. Live and dead MJ2 inhibited bone loss and afforded protection against bone erosion and joint damage in CIA mice. MJ2 decreased the levels of collagen-specific antibodies and inflammatory cytokines and the expression of osteoclast differentiation-related genes and proteins in CIA mice. Interestingly, live and dead MJ2 showed similar RA improvement effects in CIA mice. In conclusion, P. freudenreichii MJ2 inhibited osteoclast differentiation by inhibiting the NF-κB signaling pathway and ameliorated CIA.

Deficiency of sorting nexin 10 prevents bone erosion in collagen-induced mouse arthritis through promoting NFATc1 degradation

2015 ◽  
Vol 75 (6) ◽  
pp. 1211-1218 ◽  
Author(s):  
Chun Zhou ◽  
Yan You ◽  
Weixing Shen ◽  
Yi-Zhun Zhu ◽  
Jing Peng ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Osteoclast Differentiation ◽  
Critical Index ◽  
Bone Destruction ◽  
Wild Type ◽  
Clinical Role ◽  
Sorting Nexin

ObjectivePeriarticular and subchondral bone erosion in rheumatoid arthritis caused by osteoclast differentiation and activation is a critical index for diagnosis, therapy and monitoring of the disease. Sorting nexin (SNX) 10, a member of the SNX family which functions in regulation of endosomal sorting, has been implicated to play an important clinical role in malignant osteopetrosis. Here we studied the roles and precise mechanisms of SNX10 in the bone destruction of collagen-induced arthritis (CIA) mice.MethodsThe role of SNX10 in bone destruction was evaluated by a CIA mice model which was induced in male SNX10−/− mice and wild type littermates. The mechanism was explored in osteoclasts induced by receptor activator of nuclear factor κB ligand from bone marrow mononuclear cells of wild type and SNX10−/− mice.ResultsSNX10 knockout prevented bone loss and joint destruction in CIA mice with reduced serum levels of TNF-α, interleukin 1β and anticollagen IgG 2α antibody. SNX10 deficiency did not block osteoclastogenesis, but significantly impaired osteoclast maturation and bone-resorption function by disturbing the formation of actin belt. The production of TRAP, CtsK and MMP9 in SNX10−/− osteoclasts was significantly inhibited, and partially restored by SNX10 overexpression. We further demonstrated that the degradation of NFATc1 was accelerated in SNX10−/− osteoclasts causing an inhibition of integrin β3-Src-PYK2 signalling.ConclusionsOur study discloses a crucial role and novel mechanism for SNX10 in osteoclast function, and provides evidence for SNX10 as a promising novel therapeutic target for suppression of immune inflammation and bone erosion in rheumatoid arthritis.

scholarly journals GSDMD-dependent neutrophil extracellular traps formation contributes to fibroblast-like synoviocyte activation in rheumatoid arthritis

2021 ◽  
Author(s):  
Kaifeng Zhou ◽  
Chong Bian ◽  
Huijie Gu ◽  
Xiangyang Cheng ◽  
Zhongyue Huang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proinflammatory Cytokines ◽  
Peripheral Blood ◽  
Joint Damage ◽  
Bone Destruction ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps ◽  
Bovine Collagen ◽  
Blood Neutrophils

Abstract Objective The activation of NLRP3 inflammasome is critical for rheumatoid arthritis (RA), however, the role of gasdermin D (GSDMD), a newly identified pyroptosis executioner downstream of NLRP3/ASC/Caspase-1, in RA has not been well defined. Methods Genetically susceptible mice (DBA/1J) are immunized with a type II bovine collagen emulsion in complete Freund's adjuvant (CFA). Peripheral blood neutrophils were isolated from healthy volunteers and RA patients; cells were treated with serum from RA patients. The activation of GSDMD was analyzed by confocal and western blot. Proinflammatory cytokines in joint of mice were detected by qPCR and ELISA. Results The expression of cleaved GSDMD-N terminal in peripheral blood neutrophils from RA patients and the expression of GSDMD-N was positively correlated with the level of IL-1β and IL-18 from RA patients. GSDMD was required for the pathogenesis of RA, and GSDMD inhibition disulfiram significantly suppressed proinflammatory cytokines production and joint damage, leading to reduced arthritis severity score and loss of cartilage in collagen-induced arthritis (CIA) mouse model. Mechanistically, the activation of GSDMD significantly promotes neutrophil extracellular traps (NETs), which are highly immunogenic and decorated with HMGB1 and MMPs. Furthermore, GSDMD-dependent NETs formation facilitated fibroblast-like synoviocytes (FLS) activation and proliferation, driving cartilage and bone destruction, and promoting disease activity in RA. Conclusions GSDMD-dependent NETs formation promotes FLS activation during RA pathogenesis.

scholarly journals RANKL is a therapeutic target of bone destruction in rheumatoid arthritis

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 533 ◽  
Author(s):  
Sakae Tanaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Nuclear Factor Kappa B ◽  
Bone Erosion ◽  
Therapeutic Option ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Cartilage Destruction ◽  
Human Antibody ◽  
Receptor Activator ◽  
Made In

Although remarkable advances have been made in the treatment of rheumatoid arthritis (RA), novel therapeutic options with different mechanisms of action and fewer side effects have been expected. Recent studies have demonstrated that bone-resorbing osteoclasts are critically involved in the bone destruction associated with RA. Denosumab, a human antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), efficiently suppressed the progression of bone erosion in patients with RA by suppressing osteoclast differentiation and activation in several clinical studies, although it had no effect on inflammation or cartilage destruction. Denosumab, in combination with anti-rheumatic drugs, is considered a pivotal therapeutic option for the prevention of bone destruction in RA.

The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

2018 ◽  
Vol 69 (9) ◽  
pp. 2541-2545
Author(s):  
Raluca Barzoi ◽  
Elena Rezus ◽  
Codruta Badescu ◽  
Razan Al Namat ◽  
Manuela Ciocoiu
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Level Function ◽  
Rheumatoid Polyarthritis ◽  
The Impact ◽  
Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

Are neutrophil extracellular traps the link for the cross-talk between periodontitis and rheumatoid arthritis physiopathology?

Rheumatology ◽  
2021 ◽  
Author(s):  
Sicília Rezende Oliveira ◽  
José Alcides A de Arruda ◽  
Ayda Henriques Schneider ◽  
Valessa Florindo Carvalho ◽  
Caio Machado ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cross Talk ◽  
Neutrophil Extracellular Traps ◽  
Periodontal Therapy ◽  
Clinical Parameters ◽  
Extracellular Traps ◽  
Early Ra ◽  
The Cross ◽  
High Concentrations ◽  
The Impact

Abstract Objectives Neutrophil extracellular traps (NETs) play a role in the pathogenesis of periodontitis and rheumatoid arthritis (RA). However, it remains poorly understood whether NETs participate in the cross-talk between periodontitis and RA. Herein, we investigated the production of NETs in individuals with periodontitis and RA and its association with clinical parameters. The impact of periodontal therapy on RA and NET release was also assessed. Methods The concentration of NETs and cytokines was determined in the saliva and plasma of individuals with early RA (n = 24), established RA (n = 64), and individuals without RA (n = 76). The influence of periodontitis on the production of NETs and cytokines was also evaluated. Results Individuals with early RA had a higher concentration of NETs in saliva and plasma than individuals with established RA or without RA. Periodontitis resulted in an increase in the concentration of NETs of groups of individuals without RA and with early RA. The proportion of individuals with high concentrations of IL-6, IL-10 and GM-CSF was higher among individuals with periodontitis than among individuals without periodontitis. The concentrations of TNF-α, IL-6, IL-17/IL-25, and IL-28A were particularly high in individuals with early RA. Worse periodontal clinical parameters, RA onset and RA activity were significantly associated with circulating NETs. Periodontal therapy was associated with a reduction in the concentration of NETs and inflammatory cytokines and amelioration in periodontitis and RA. Conclusion This study reveals that NETs are a possible link between periodontitis and RA, with periodontal therapy resulting in a dramatic switch in circulating NET levels.

scholarly journals AB0048 ENZYMATIC PATTERN OF CIRCULATING PRO- AND ANTIOXIDANT ENZYMES IN RHEUMATOID ARTHRITIS PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1056.2-1057
Author(s):  
S. Bedina ◽  
E. Mozgovaya ◽  
A. Trofimenko ◽  
S. Spitsina ◽  
M. Mamus
Keyword(s):  
Rheumatoid Arthritis ◽  
Antioxidant Enzymes ◽  
Disease Activity ◽  
Neutrophil Extracellular Traps ◽  
Unknown Etiology ◽  
Antioxidant Enzyme Activities ◽  
Reference Ranges ◽  
Sod Activity ◽  
Low Disease Activity ◽  
Extracellular Traps

Background:Rheumatoid arthritis (RA) is an autoimmune rheumatic disease of unknown etiology characterized by chronic erosive arthritis and systemic organ involvement resulting in early disability and shorter life expectancy. Neutrophils are suggested to play a substantial role in the induction and promotion of autoimmune inflammation in RA. This ability can be based on newly discovered feature of neutrophils to release neutrophil extracellular traps (NETs) during specific type cell death called NETosis. Hyperproduction of reactive oxygen species (ROS) is one of the factors promoting NETs production. With this background, the study of pro- and antioxidant enzymatic activities in RA patients can be of great interest.Objectives:To assess plasma activities of essential prooxidant and antioxidant enzymes in RA patients.Methods:The research was carried out in agreement with the WMA Declaration of Helsinki principles. 71 RA patients (46 women and 25 men) were enrolled in the study. The diagnosis was verified using ACR/EULAR criteria (2010). RA activity was measured using the Disease Activity Score of 28 joints (DAS28). 30 healthy persons comprise control group. Plasma xanthine oxidase (XO; ЕС 1.17.3.2), xanthine dehydrogenase (XDH; ЕС 1.17.1.4) and superoxide dismutase (SOD; ЕС 1.15.1.1) activities were measured using spectrophotometric technique. XO and XDG activities were expressed as nmol/ml/min, SOD activity – as units of action. Statistical analysis was performed using Statistica 6.0 software package. Differences were considered significant when p<0.05. Reference ranges were calculated as means ±2SD.Results:Mean age of patients was 43.2±3.6 years, mean RA duration was 11.9±2.6 years. 24 (33.8%) RA patients had low disease activity, and 6 (8.5%) patients had high one. Extra-articular manifestations were found in 30 (42.2%) patients. 30% of them had cardiovascular involvement, 23.3% – pulmonary lesions, and 23.3% had renal involvement. Reference ranges for XO, XDG, and SOD activities were 2.28-5.12 nmol/min/ml, 3,96-7,24 nmol/min/ml, and 3,13-6,58 units, respectively. We examined activities of these enzymes in circulation of RA patients with different patterns of clinical manifestations as well as relationship between RA activity and XO, XDG, and SOD activities. RA patients had increased both mean XO and mean SOD activities (p<0.001 for both enzymes). XO activity reached its highest values at maximum disease activity and overt extra-articular involvements, while SOD activity did it in moderate and high disease activities as well as in patients with joint manifestations. XDG activity was increased in low disease activity (р<0.001) and solely joint lesions (р=0.011), while moderate or high disease activities (р=0.008) and extra-articular involvements (р=0.025) were characterized by decreased activity of this enzyme.Conclusion:We have revealed substantial multidirectional changes of plasma XO and XDG activities in RA. Plasma enzymatic pattern in RA patients is characterized by activation of both oxidant and antioxidant metabolic pathways. Activities of XO and SOD were positively correlated with RA activity, while XDG activity was negative correlated with RA activity. The differences between selective articular RA type and RA form with extraarticular manifestations were also revealed. Changes in oxidant and antioxidant enzyme activities can be connected with anticitrulline autoimmunity in RA via production of citrulline-rich neutrophil extracellular traps, thus enhancing rheumatoid autoimmunity.Disclosure of Interests:None declared

scholarly journals Nanomaterial Exposure Induced Neutrophil Extracellular Traps: A New Target in Inflammation and Innate Immunity

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Hang Yang ◽  
Tony N. Marion ◽  
Yi Liu ◽  
Lingshu Zhang ◽  
Xue Cao ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Immune Responses ◽  
Myeloid Cell ◽  
Neutrophil Extracellular Traps ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Cell Type ◽  
Extracellular Traps ◽  
Pharmaceutical Industries ◽  
The Relationship

Nanotechnology has become a novel subject with impact in many research and technology areas. Nanoparticles (NPs), as a key component in nanotechnology, are widely used in many areas such as optical, magnetic, electrical, and mechanical engineering. The biomedical and pharmaceutical industries have embraced NPs as a viable drug delivery modality. As such, the potential for NP-induced cytotoxicity has emerged as a major concern for NP drug delivery systems. Thus, it is important to understand how NPs affect the innate immune system. As the most abundant myeloid cell type in innate immune responses, neutrophils are critical for concerns about potentially toxic side effects of NPs. When activated by innate immune stimuli, neutrophils may initiate NETosis to release neutrophil extracellular traps (NETs). Herein, we have reviewed the relationship between NPs and the induction of NETosis and release of NETs.

Antibodies toPorphyromonas gingivalisAre Associated with Anticitrullinated Protein Antibodies in Patients with Rheumatoid Arthritis and Their Relatives

2010 ◽  
Vol 37 (6) ◽  
pp. 1105-1112 ◽  
Author(s):  
CAROL A. HITCHON ◽  
FATIHA CHANDAD ◽  
ELIZABETH D. FERUCCI ◽  
ANNEMIEK WILLEMZE ◽  
ANDREEA IOAN-FACSINAY ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Responses ◽  
Rheumatoid Factor ◽  
Porphyromonas Gingivalis ◽  
Immune Tolerance ◽  
Oral Hygiene ◽  
Shared Epitope ◽  
Poor Oral Hygiene ◽  
Citrullinated Peptide ◽  
Anticitrullinated Protein Antibodies

Objective.Anticitrullinated protein antibodies (ACPA) are relatively specific for rheumatoid arthritis (RA), and predate disease. The oral pathogenPorphyromonas gingivalismay play a role in breaking immune tolerance to citrullinated antigens. We studied a cohort of patients with RA and their relatives looking for associations between anti-P. gingivalisantibodies and ACPA.Methods.Patients with RA (n = 82) and their relatives (n = 205) from a North American Native (NAN) population were studied, along with 47 NAN and 60 non-NAN controls. IgM and IgA rheumatoid factor (RF) were tested by nephelometry and ELISA. Second-generation anticyclic citrullinated peptide (anti-CCP2) isotypes and IgG anti-P. gingivalislipopolysaccharides were tested by ELISA. HLA-DRB1 typing was performed by sequencing. Oral hygiene and smoking habits were assessed by questionnaires.Results.Autoantibody frequency in patients with RA and relatives: ACPA 91% vs 19%, respectively; IgM RF 82% vs 17%; IgA RF 48% vs 22%. Anti-P. gingivalislevels were higher in patients with RA compared to relatives and controls (p = 0.005) and higher in ACPA-positive patients with RA than in ACPA-negative patients with RA (p = 0.04) and relatives (p < 0.001), but comparable in RF-positive and RF-negative patients and relatives. Poor oral hygiene and smoking were prevalent, but with no clear association with autoantibodies. Relatives with 2 shared-epitope alleles were more likely to be ACPA-positive (OR 2.5, p = 0.02).Conclusion.In a genetically predisposed population of NAN patients with RA and their relatives, anti-P. gingivalisantibodies were associated with ACPA. These findings suggest that immune responses toP. gingivalismay be involved in breaking immune tolerance to citrullinated antigens.

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