Activation of DR3 signaling causes loss of ILC3s and exacerbates intestinal inflammation

Jingyu Li,Huiming Sheng,Ting Cai,Jie Shu,Hanxiao Sun,Yan Ji,Liang Zhou,Wenli Shi,Yuqin Chen,Ju Qiu,Xiaohuan Guo

doi:10.1038/s41467-019-11304-8

Abstract

TNF-like ligand 1 A (TL1A) and death receptor 3 (DR3) are a ligand-receptor pair involved in the pathogenesis of inflammatory bowel disease. Group 3 innate lymphoid cells (ILC3s) regulate intestinal immunity and highly express DR3. Here, we report that activation of DR3 signaling by an agonistic anti-DR3 antibody increases GM-CSF production from ILC3s through the p38 MAPK pathway. GM-CSF causes accumulation of eosinophils, neutrophils and CD11b+CD11c+ myeloid cells, resulting in loss of ILC3s from the intestine in an IL-23-dependent manner and exacerbating colitis. Blockade of GM-CSF or IL-23 reverses anti-DR3 antibody-driven ILC3 loss, whereas overexpression of IL-23 induces loss of ILC3s in the absence of GM-CSF. Neutralization of TL1A by soluble DR3 ameliorates both DSS and anti-CD40 antibody-induced colitis. Moreover, ILC3s are required for the deleterious effect of anti-DR3 antibodies on innate colitis. These findings clarify the process and consequences of DR3 signaling-induced intestinal inflammation through regulation of ILC3s.

Highlights

TNF-like ligand 1 A (TL1A) and death receptor 3 (DR3) are a ligand-receptor pair involved in the pathogenesis of inflammatory bowel disease
TL1A is mainly expressed by antigen presenting cells upon stimulation with Toll-like receptor (TLR) ligands or immune complexes[2], whereas DR3 is broadly expressed by lymphocytes, including CD4+ T cells, CD8+ T cells, invariant natural killer T cells, and innate lymphoid cells (ILCs)[1,3]
We have further proved that p38 signaling is essential for GM-CSF production by ILC3s induced by TL1A/DR3 signaling in both mice and humans

Summary

Introduction

TNF-like ligand 1 A (TL1A) and death receptor 3 (DR3) are a ligand-receptor pair involved in the pathogenesis of inflammatory bowel disease. ILC3s are required for the deleterious effect of anti-DR3 antibodies on innate colitis. These findings clarify the process and consequences of DR3 signaling-induced intestinal inflammation through regulation of ILC3s. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China. In addition to the pro-inflammatory aspect, activation of TL1A/DR3 signaling has an immunosuppressive role through expansion of T-regulatory cells (Tregs)[4]. This effect can be achieved by administration of an agonistic antibody against. DR3 or TL1A are susceptible to dextran sulfate sodium (DSS)induced colitis accompanied by reduced number of Tregs[11]

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