Loss of TIPE2 Has Opposing Effects on the Pathogenesis of Autoimmune Diseases.

Ruiling Liu,Ting Wang,Qingguo Ruan,Wenwen Geng,Xiaozhen He

doi:10.3389/fimmu.2019.02284

Abstract

Autoimmune diseases are a physiological state wherein immune responses are directed against and damage the body's own tissues. Cytokines secreted by infiltrated inflammatory cells contribute to the pathogenesis of autoimmune diseases. TIPE2, one of the four family members of Tumor necrosis factor-α induced protein-8 (TNFAIP8), is a negative regulator of innate and adaptive immunity and plays essential roles in the maintenance of immune tolerance. However, studies on the role of TIPE2 during the development of autoimmune diseases have generated contradictory results. In the current study, we sought to determine the role of TIPE2 during the development of IMQ-induced psoriasis and Experimental Autoimmune Uveitis (EAU) in mice. Our study revealed that, while TIPE2-deficiency alleviates psoriasis, it exacerbates the development of EAU. Further studies demonstrated that, although TIPE2-deficient T cells produced more IL-17A, they do not migrate efficiently to the local inflammatory site, i.e., the skin. This in turn led to the decreased IL-17A production in the skin and consequently reduced the severity of psoriasis in TIPE2-deficient mice. However, although TIPE2-deficient T cells still produced more IL-17A in EAU model, they migrate into the inflamed eye as efficient as TIPE2-sufficient T cells, and consequently exacerbates the development of EAU in TIPE2-deficient mice. Taken together, these results indicate that TIPE2 may either promote or suppress autoimmunity depending on the specific inflammatory microenvironment in different types of autoimmune diseases.

Highlights

Autoimmune disease occurs when healthy body tissues were mistakenly attacked and destroyed by body’s own immune system
In order to determine the roles of TIPE2 in the pathogenesis of different types of autoimmune diseases, we established IMQ-induced psoriasis model and Experimental Autoimmune Uveitis (EAU) model in wild-type and TIPE2-deficient mice in the C57BL/6 background
We found that mice received TIPE2-deficient T cells developed less severe symptoms than those reconstituted with WT T cells (Figure 1B)

Summary

Introduction

Autoimmune disease occurs when healthy body tissues were mistakenly attacked and destroyed by body’s own immune system. More than 80 types of different autoimmune diseases have been reported, including psoriasis, Experimental Autoimmune Uveitis (EAU), type 1 diabetes, Experimental Autoimmune Encephalomyelitis (EAE), and Rheumatoid Arthritis (RA). Besides genetic and environmental factors, immunological factor often plays important roles during the pathogenesis of autoimmune disease which triggers the initiation of the disease as well as maintaining the disease state [1, 2]. T cells, especially the IL-17A-producing Th17 cells, have been shown to play a dominant role during the pathogenesis of multiple autoimmune diseases including psoriasis and EAU [3,4,5,6,7,8]. While IL-17A knockout mice develop significantly less severe psoriasis and EAU [10, 11], treatment with anti-IL17A antibody markedly reduced inflammation in both psoriatic and EAU mice [12,13,14]

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Results

Conclusion