IL-33/ST2-mediated inflammation in macrophages is directly abrogated by IL-10 during rheumatoid arthritis.

Si Chen,Bingni Chen,Zhong Huang,Zhongyang Wen,Liang Ye

doi:10.18632/oncotarget.16299

Abstract

IL-10 is an immunosuppressive cytokine produced and sensed by many immune cells and exerts a protective role in autoimmune diseases. However, the underlying mechanism by which IL-10 contributes to prevent the arthritic inflammation in macrophages is poorly understood. Herein we report on a novel anti-arthritic property of IL-10 through the inhibition of IL-33 signaling by macrophages during collagen-induced arthritis (CIA) development. We show that IL-33 expression rather than its receptor (ST2) is positively correlated with IL-10 level in active RA. IL-10 deficiency in mice leads to significant upregulation of IL-33 expression and aggravates the progression of CIA, while exogenous IL-10 treatment effectively diminishes IL-33 production in IL-10 knockout (IL-10−/−) CIA mice. We demonstrate further that the inhibitory effect of IL-10 in suppressing IL-33 production requires STAT3 activation in macrophages. Furthermore, IL-33 stimulated proinflammatory genes are notably increased in IL-10−/− CIA mice, whereas macrophages treated with recombinant IL-10 exhibit decreased IL-33 amplified inflammation and inhibited IL-33 activated NF-κB signaling pathway. Our findings indicate that IL-10 act as a negative regulator of IL-33/ST2 signaling pathways in vivo, suggesting a potential therapeutic role of IL-10 in autoimmune diseases.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by inflammatory cells infiltration of the joint, leading to cartilage and bone destruction [1]
To extend the knowledge about the previously reported that upregulated IL-33 and ST2 expression and increased IL-10 production could be detected in patients with RA and involved in the pathogenesis of RA [8, 14], we initially wanted to investigate the possible correlation between IL-33/ST2 and IL-10 in RA
We found that serum IL33 levels in active RA patients were positively correlated with IL-10 expression (Figure 1G), but no significant correlation was determined in all RA patients

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by inflammatory cells infiltration of the joint, leading to cartilage and bone destruction [1]. Dysregulated macrophage responses have been shown to contribute to many autoimmune pathogenesis by the production of proinflammatory cytokines such as IL-33, ST2 and IL-1β, as well as proinflammatory chemokine MCP-1 production [2, 3, 4] Remarkably, depletion of macrophages alleviates the symptoms and severity of collagen-induced arthritis (CIA) in mice [5]. The frequency of macrophages is markedly elevated in the inflamed synovial tissues of patients with RA and positively correlated with disease pathogenesis and progression [6]. Activated ST2 signaling by extracellular IL33 may result in activation of NF-κB and MAPK (P38, ERK and JNK) in macrophages leading to a potential induction of pro-inflammatory cytokines (IL-1β) and chemokines (MCP-1) [7]. Recent reports have found increased IL-33 and ST2 production in the serum and synovial tissue of patients with RA [8, 9]

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