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

Jingyu Li, Wenli Shi, Hanxiao Sun, Yan Ji, Yuqin Chen, Xiaohuan Guo, Huiming Sheng, Jie Shu, Liang Zhou, Ting Cai and Ju Qiu ()
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Jingyu Li: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Wenli Shi: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hanxiao Sun: Shanghai Jiao Tong University School of Medicine
Yan Ji: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yuqin Chen: Shanghai Jiao Tong University School of Medicine
Xiaohuan Guo: Tsinghua University
Huiming Sheng: Shanghai Jiao Tong University School of Medicine
Jie Shu: Shanghai Jiao Tong University School of Medicine
Liang Zhou: The University of Florida
Ting Cai: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ju Qiu: University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11304-8

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