Tumor necrosis factor-like cytokine 1A plays a role in inflammatory bowel disease pathogenesis

Fanxiang Meng; Xuefeng Jiang; Xiao Wang; Qianqian Zheng; Xiaonan N Wang; Chenxue Mei; Siqi Yan; Yuting He; Junxiu Xue; Xiaoqing Zhang; Wenda Fu; Yong You; Jingbo Zhai; Yuanyuan Wang; Xun Sun

doi:10.1073/pnas.2120771120

Tumor necrosis factor-like cytokine 1A plays a role in inflammatory bowel disease pathogenesis

Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2120771120. doi: 10.1073/pnas.2120771120. Epub 2023 Aug 14.

Authors

Fanxiang Meng^#^{1

2}, Xuefeng Jiang^#¹, Xiao Wang¹, Qianqian Zheng³, Xiaonan N Wang¹, Chenxue Mei^{1

4}, Siqi Yan¹, Yuting He¹, Junxiu Xue¹, Xiaoqing Zhang^{1

5}, Wenda Fu^{1

6}, Yong You^{1

7}, Jingbo Zhai^{8

9}, Yuanyuan Wang¹⁰, Xun Sun¹

Affiliations

¹ Department of Immunology, Basic Medicine College, China Medical University, Shenyang, Liaoning Province 110122, China.
² Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, Liaoning Province 110801, China.
³ Department of Pathophysiology, Basic Medicine College, China Medical University, Shenyang, Liaoning Province 110122, China.
⁴ Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110122, China.
⁵ Teaching Center for Medical Experiment, China Medical University, Shenyang, Liaoning Province 110122, China.
⁶ Department of Blood Transfusion, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, China.
⁷ Department of Immunology, Chengde medical university, Chengde, Hebei Province 067000, China.
⁸ Medical College, Inner Mongolia Minzu University, Tongliao 028000, China.
⁹ Key Laboratory of Zoonose Prevention and Control at Universities of Inner Mongolia Autonomous Region, Tongliao 028000, China.
¹⁰ Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110032, China.

^# Contributed equally.

Abstract

The binding of tumor necrosis factor-like cytokine 1A (TL1A) to death receptor 3 (DR3) plays an important role in the interaction between dendritic cells (DCs) and T cells and contributes to intestinal inflammation development. However, the mechanism by which DCs expressing TL1A mediate helper T (Th) cell differentiation in the intestinal lamina propria (LP) during the pathogenesis of inflammatory bowel disease remains unclear. In this study, we found that TL1A/DR3 promoted Th1 and Th17 cell differentiation in T-T and DC-T cell interaction-dependent manners. TL1A-deficient CD4⁺ T cells failed to polarize into Th1/Th17 cells and did not cause colonic inflammation in a T cell transfer colitis model. Notably, TL1A was located in the cytoplasm and nuclei of DCs, positively regulated the DC-specific ICAM-grabbing nonintegrin/RAF1/nuclear factor κB signaling pathway, enhanced the antigen uptake ability of DCs, and promoted TLR4-mediated DC activation, inducing naive CD4⁺ T cell differentiation into Th1 and Th17 cells. Our work reveals that TL1A plays a regulatory role in inflammatory bowel disease pathogenesis.

Keywords: TL1A; dendritic cell; inflammatory bowel disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Inflammation / metabolism
Inflammatory Bowel Diseases* / metabolism
Receptors, Tumor Necrosis Factor, Member 25 / metabolism
Tumor Necrosis Factor Ligand Superfamily Member 15* / genetics
Tumor Necrosis Factor Ligand Superfamily Member 15* / metabolism
Tumor Necrosis Factor-alpha

Substances

Tumor Necrosis Factor Ligand Superfamily Member 15
Receptors, Tumor Necrosis Factor, Member 25
Tumor Necrosis Factor-alpha