Activated IL-1RI Signaling Pathway Induces Th17 Cell Differentiation via Interferon Regulatory Factor 4 Signaling in Patients with Relapsing-Remitting Multiple Sclerosis.

Yonggang Sha,Silva Markovic-Plese

doi:10.3389/fimmu.2016.00543

Yonggang Sha, Silva Markovic-Plese

Open Access

https://doi.org/10.3389/fimmu.2016.00543

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Abstract

IL-1β plays a crucial role in the differentiation of human Th17 cells. We report here that IL-1RI expression is significantly increased in both naive and memory CD4+ T cells derived from relapsing-remitting multiple sclerosis (RR MS) patients in comparison to healthy controls. Interleukin 1 receptor (IL-1R)I expression is upregulated in the in vitro-differentiated Th17 cells from RR MS patients in comparison to the Th1 and Th2 cell subsets, indicating the role of IL-1R signaling in the Th17 cell differentiation in RR MS. When IL-1RI gene expression was silenced using siRNA, human naive CD4+ T cells cultured in the presence of Th17-polarizing cytokines had a significantly decreased expression of interleukin regulatory factor 4 (IRF4), RORc, IL-17A, IL-17F, IL-21, IL-22, and IL-23R genes, confirming that IL-1RI signaling induces Th17 cell differentiation. Since IL-1R gene expression silencing inhibited IRF4 expression and Th17 differentiation, and IRF4 gene expression silencing inhibited Th17 cell differentiation, our results indicate that IL-1RI induces human Th17 cell differentiation in an IRF4-dependant manner. Our study has identified that IL-1RI-mediated signaling pathway is constitutively activated, leading to an increased Th17 cell differentiation in IRF4-dependent manner in patients with RR MS.

Highlights

IL-1β induces differentiation of T helper (Th) 17 cells, which play a critical role in the development of the autoimmune response
We found an increased IL-1RI gene expression in CD4+, CD4+CD45RA+, and CD4+CD45RO+ cells derived from RR relapsing-remitting multiple sclerosis (MS) patients in comparison to healthy controls (HCs) (Figure 1)
The results revealed that IL-17A, IL-17F, IL-21, and IL-22 secretion induced in naive CD4+ cells derived from the HCs in the presence of Th17-polarizing cytokines were significantly suppressed upon silencing of their IL-1RI expression (Figure 4A)

Summary

Introduction

IL-1β induces differentiation of T helper (Th) 17 cells, which play a critical role in the development of the autoimmune response. IL-1β contributes to IL-6-induced RORc expression and IL-17A production in humans [1, 2], consistent with animal studies in which IL-1β has a synergistic effect with IL-23 in promoting Th17 differentiation [3, 4]. The role of IL-17 in MS and other autoimmune disorders has been demonstrated in multiple studies. IL-17 mRNA and protein expression is Abbreviations: EAE, experimental autoimmune encephalomyelitis; HCs, healthy controls; IL-1R, interleukin-1 receptor; IRF, interferon regulatory factor; PBMCs, peripheral blood mononuclear cells; RR MS, relapsing-remitting multiple sclerosis; SNs, supernatants, TCR, T cell receptor. IL-17 has been detected in the target organs of other autoimmune diseases, including rheumatoid arthritis, psoriasis, and autoimmune uveitis [8], suggesting its role in human autoimmune responses

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