Synovial fibroblasts have emerged as critical underlying factors to perpetuate chronic joint inflammation in Rheumatoid Arthritis. Like any other cell, synovial fibroblasts are covered with a complex layer of glycans that can change in response to extracellular signals, such as inflammation. We have previously shown that inflammatory synovial fibroblasts show decreased levels of sialic acid, but our understanding of sialic acid-dependent pathophysiological pathways in these stromal cells is still very limited. In this report, we used in vivo and in vitro studies with exogenous sialidases and RNA sequencing to investigate the responses of murine synovial fibroblasts upon desialylation. Our results show that hyposialylated fibroblasts present a dysregulated migratory ability and an activated phenotype characterized by the expression of inflammatory mediators, such as cytokines and chemokines, and anti-viral related mechanisms. Removal of surface sialic acid also affected the expression of sialyltransferases, revealing the existence of a positive feedback to sustain reduced sialylation. Moreover, we demonstrate that synovial fibroblasts subsets have distinct sialyltransferase expression profiles, both in healthy and arthritic mice. These findings underline the ability of sialic acid to modulate homeostatic and inflammatory responses in non-immune synovial fibroblasts, suggesting that sialylation plays a key role in perpetuating local inflammation in the arthritic joint.
CD20+ T cells comprise a small but highly inflammatory subset that has been implicated in autoimmunity, including rheumatoid arthritis (RA). We sought to characterise the CD20+ T cell subset at the site of inflammation in murine collagen-induced arthritis (CIA) model of RA and investigate the phenotype and functional relevance of CD3+CD20+ T cells in the lymph nodes and arthritic joints using flow cytometry and immunohistochemistry. We demonstrate that CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells are expanded in the draining lymph nodes of CIA mice. In addition, compared to naïve mice and those that did not develop clinical symptoms, CD20 expressing T cells of arthritic mice produced increased levels of pro-inflammatory cytokines (GM-CSF, TNF-a, IL-17, and INF-g). Notably, CD3+CD4+CD20+ and CD3+CD8+CD20+ T cells of disease mice were enriched with CXCR5+PD-1+ T follicular helper cells and CXCR5-PD-1+ peripheral T helper cells, subsets of T cells that have been implicated in promoting B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues in RA. Importantly, CD3+CD20+ T cells were detected in the inflamed regions in the lymph nodes and paws of arthritic mice. Our findings suggest that CD20+ T cells are associated with inflammatory responses in the arthritic joint and may exacerbate pathology by promoting inflammatory B cell responses.
Objective Undenatured Type II Collagen (Lonza's UC‐II® branded ingredient, Lonza) shows an ability to reduce inflammation of rheumatoid arthritis (RA) and osteoarthritis through oral tolerance, but the mechanisms underlying this protective effect remain unclear. Our goal is to understand how changes in the gut microenvironment affect tolerogenic responses upon oral administration of UC‐II® supplementation. Hypothesis We hypothesize that systemic inflammation during inflammatory arthritis regulate local tolerogenic responses and inflammation. Identification and further intervention of these pathways may be a promising way to improve the therapeutic activity of UC‐II® ingredient. Methods Murine Collagen‐Induced Arthritis (CIA) was employed as a model of human RA. Mice with CIA were treated with UC‐II® supplementation or vehicle by oral gavage (0.66 mg/kg and 5.94 mg/kg for 8 weeks, starting 2 weeks before CIA induction). Incidence and clinical scores were monitored throughout the study period. Animals were culled at week 9, when blood, tissues (gut and lymph nodes) and paws were collected. Histopathological scores were carried out, including H&E staining of gut tissue and paws. Additionally, pro‐inflammatory cytokine IL‐17 and IgGs against collagen were evaluated by ELISA. Immune cell populations in mesenteric lymph nodes (MLNs) and draining lymph nodes (DLNs) were evaluated by flow cytometry. Finally, RT‐PCR was carried out to evaluate expression of inflammatory genes. Results Mice treated with 5.94 mg/kg UC‐II® supplementation showed a reduced disease incidence compared with CIA control mice, although clinical scores were not altered. However, histological analysis of the joints indicated that UC‐II® administration reduced cartilage and bone damage. Interestingly, UC‐II® reverted the reduction of villi length observed in the small intestine of CIA control animals. UC‐II® treatment affected local and systemic immune responses, since numbers of CD4 T cells, CD8 T cells and B cells in joint draining and mesenteric lymph nodes were significantly modulated. Inflammatory responses were attenuated in UC‐II® treated mice, evidenced by a reduction in serum antibodies against collagen and a strong reduction in IL‐17 expression. Conclusions UC‐II® supplementation protected against cartilage and bone damage during murine experimental arthritis. This could be possibly attributed to reduced expression of IL‐17. Blocking of IL‐17 pathway has been shown to have a positive effect on bone and cartilage damage in inflammatory arthritis. Our data suggest that oral administration of UC‐II® supplementation could represent a novel approach to target this pathway in chronic inflammation. Further understanding of the molecular mechanisms triggered in the gut tissue during RA may pave the way for optimization of UC‐II®.
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