Synovial IL-9 facilitates neutrophil survival, function and differentiation of Th17 cells in rheumatoid arthritis

Kaustav Chowdhury,Santu Bandyopadhaya,Ravi Kiran Basyal,Geetabali Sircar,Prabin Kumar,Uma Kumar,Soumabha Das,Parashar Ghosh,Dipendra Kumar Mitra,Uma Kanga,Maumita Kanjilal,Jaydeep Chaudhuri

doi:10.1186/s13075-017-1505-8

Abstract

BackgroundRole of Th9 cells and interleukin-9 (IL-9) in human autoimmune diseases such as psoriasis and ulcerative colitis has been explored only very recently. However, their involvement in human rheumatoid arthritis (RA) is not conclusive. Pathogenesis of RA is complex and involves various T cell subsets and neutrophils. Here, we aimed at understanding the impact of IL-9 on infiltrating immune cells and their eventual role in synovial inflammation in RA.MethodsIn vitro stimulation of T cells was performed by engagement of anti-CD3 and anti-CD28 monoclonal antibodies. Flow cytometry was employed for measuring intracellular cytokine, RORγt in T cells, evaluating apoptosis of neutrophils. ELISA was used for measuring soluble cytokine, Western blot analysis and confocal microscopy were used for STAT3 phosphorylation and nuclear translocation.ResultsWe demonstrated synovial enrichment of Th9 cells and their positive correlation with disease activity (DAS28-ESR) in RA. Synovial IL-9 prolonged the survival of neutrophils, increased their matrix metalloprotienase-9 production and facilitated Th17 cell differentiation evidenced by induction of transcription factor RORγt and STAT3 phosphorylation. IL-9 also augmented the function of IFN-γ + and TNF-α + synovial T cells.ConclusionsWe provide evidences for critical role of IL-9 in disease pathogenesis and propose that targeting IL-9 may be an effective strategy to ameliorate synovial inflammation in RA. Inhibiting IL-9 may have wider impact on the production of pathogenic cytokines involved in autoimmune diseases including RA and may offer better control over the disease.

Highlights

Role of Th9 cells and interleukin-9 (IL-9) in human autoimmune diseases such as psoriasis and ulcerative colitis has been explored only very recently
Our study demonstrates that (i) Th9 cells are enriched in synovial fluid (SF), (ii) SF IL-9 drives the inflammatory cascade by inhibiting apoptosis of neutrophils and production of matrix metalloproteinase-9 (MMP-9) and (iii) augments the differentiation of Th17 cells in rheumatoid arthritis (RA)-affected synovia
Enrichment of Th9 cells in the RA SF correlates with disease activity score (DAS28-erythrocyte sedimentation rate (ESR)) We aimed to enumerate the frequency of IL-9-producing CD4+ T cells in peripheral blood (PBL) and SF of RA patients by flow cytometry

Summary

Introduction

Role of Th9 cells and interleukin-9 (IL-9) in human autoimmune diseases such as psoriasis and ulcerative colitis has been explored only very recently. Helper T (CD4+) cells preferentially producing interleukin (IL)-9 have recently been described as distinct Th9 cells and implicated in several inflammatory conditions such as infectious, neoplastic and autoimmune diseases [1,2,3,4]. Contribution of these cells in the pathogenesis of autoimmunity has been demonstrated in animal studies of colitis [5, 6], uveitis [7], and experimental autoimmune encephalomyelitis (EAE) [8,9,10]. Elucidating functional hierarchy of distinct effector T cells producing key pathogenic cytokine(s) is critical and may provide novel opportunity for modulating inflammation in RA and disease remission

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