TRAIL suppresses gut inflammation and inhibits colitogeic T-cell activation in experimental colitis via an apoptosis-independent pathway

I.T Chyuan,P.N Hsu,H.F Tsai,C.S Wu

doi:10.1038/s41385-019-0168-y

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals. Recently, accumulating evidence demonstrated that TRAIL regulates autoimmune inflammation and immune cell homeostasis in several autoimmune animal models, suggesting a novel immunoregulatory role of TRAIL in autoimmune diseases. However, the impact of TRAIL in inflammatory bowel disease is yet undefined. This study is to address the therapeutic effects and immunoregulatory role of TRAIL in autoimmune gut inflammation. We demonstrated herein that TRAIL significantly suppressed gut inflammation and reduced the severity of colitis in a dextran sodium sulfate (DSS)-induced colitis model. Suppression of gut inflammation was not due to induction of apoptosis in colonic T cells, dendritic cells, or epithelium cells by TRAIL. In contrast, TRAIL directly inhibited activation of colitogenic T cells and development of gut inflammation in an adoptive transfer-induced colitis model. The anti-inflammatory effects of TRAIL on colitis were abolished when T cells from TRAIL receptor (TRAIL-R) knockout mice were adoptively transferred, suggesting that TRAIL regulates autoreactive colitogenic T-cell activation in the development of gut inflammation. Our results demonstrate that TRAIL effectively inhibited colonic T-cell activation and suppressed autoimmune colitis, suggesting a potential therapeutic application of TRAIL in human inflammatory bowel disease.

Highlights

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that preferentially induces cell apoptosis in a variety of transformed cell lines.[1]
A previous study demonstrated that Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced human intestinal epithelial cell apoptosis under inflammatory conditions, while it did not induce enterocyte apoptosis in normal noninflammatory conditions,[16] suggesting that TRAIL contributes to the pathogenesis of gut inflammation
In this study, we demonstrated that TRAIL directly inhibited gut inflammation and reduced the severity of colitis in animal models of autoimmune colitis, and these effects were dependent on the TRAIL receptor (TRAIL-R)

Summary

Introduction

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that preferentially induces cell apoptosis in a variety of transformed cell lines.[1]. Recent accumulating evidence in several autoimmune animal models suggests an immunoregulatory role of TRAIL in controlling inflammation in autoimmune diseases. TRAIL blockade[7] or a TRAIL deficiency 8 enhanced disease activity and increased joint inflammation. Similar findings were observed in mice with experimental autoimmune encephalomyelitis (EAE).[9] Recent studies further demonstrated that administration of TRAIL is effective in suppressing autoimmune inflammation via an apoptosis-independent pathway.[10,11] All these results imply a novel immunoregulatory role of TRAIL in autoimmune diseases

Methods

Results

Conclusion