CysLT1 receptor antagonist alleviates pathogenesis of collagen-induced arthritis mouse model.

Minwen Xu,Liefeng Wang,Xiaoli Zhang,Yi Zhang,Hailin Zou,Zhiping Hou,Ruiyun Hong

doi:10.18632/oncotarget.22664

Abstract

Cysteinyl leukotrienes (CysLTs) play a key role in inflammatory diseases such as asthma and their receptors’ antagonists are currently used as anti-asthmatic drugs. CysLTs have also been found to participate in other inflammatory reactions. Here, we reported that in rheumatoid arthritis (RA) animals model, collagen-induced arthritis, (CIA), CysLT1, a receptor for CysLTs, was up-regulated in hind paw and lymph node, while CysLTs levels in the blood were also higher than normal mice. Montelukast, a drug targeting CysLT1, has been shown to effectively reduce the CIA incidence, peak severity, and cumulative disease scores. Further study indicated that CysLT1 signaling did not affect the differentiation of pathogenic T helper cells. We conclude that montelukast may play important roles in the pathogenesis of CIA, mainly by inducing infiltration of pathogenic T cells, increasing IL-17A secretion and expression of IL-17A, while these effects can be blocked by CysLT1 antagonists. Our findings indicate that antagonist of CysLT1 receptor may be used to treat rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune-mediated synovitis, local inflammatory cells infiltration and neoangiogenesis [1, 2]
We demonstrated that Cysteinyl leukotrienes (CysLTs) signaling pathway play a vital role in the pathogenesis of CIA, primarily by up-regulating the expression of IL-17A gene, inducing production of IL-17A, and infiltration of pathogenic T cells which can be relieved by blocked CysLT1 signaling pathway
To describe the role CysLTs played in the pathogenesis of CIA, we firstly detected the mRNA levels of key ingredients in CysLT1 signaling pathways, including the receptor CysLT1 and three CysLTs synthesizing enzymes in hind paw and lymph node at week 0, 3, 6, 9, 12, 15 post booster immunization (Figure 1 and Supplementary Figure 1)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by immune-mediated synovitis, local inflammatory cells infiltration and neoangiogenesis [1, 2]. The etiology of the disease remains unclear, it is considered a complex chronic disorder which inflammatory mediators played a crucial role in the rheumatoid synovium and synovial fluid [3]. IL-17 receptors are positive in progenitor cells from RA cartilage, IL-17A/F increase the RUNX2 and IL-6 protein expression levels and up-regulate the MMP3 mRNA expression levels. Anti IL-17 antibody reduced the secretion of IL-6 protein level and increased the secretion of IL-10 protein level [5]. Knocking out IL-17A or treatment with anti IL17 antibodies or blocking IL-17 receptor may alleviate arthritis [6,7,8]. More clinical trials are need to confirm those effect since occasionally contradictory results with IL-17 were found in certain RA models [9]

Methods

Results

Conclusion