HMGB1 exacerbates experimental mouse colitis by enhancing innate lymphoid cells 3 inflammatory responses via promoted IL-23 production.
In inflammatory bowel diseases (IBD), high mobility group box 1 (HMGB1), as an endogenous inflammatory molecule, can promote inflammatory cytokines secretion by acting on TLR2/4 resulting in tissue damage. The underlying mechanisms remain unclear. Here we report a novel role of HMGB1 in controlling the maintenance and function of intestine-resident group-3 innate lymphoid cells (ILC3s) that are important innate effector cells implicated in mucosal homeostasis and IBD pathogenesis. We showed that mice treated with anti-HMGB1 Ab, or genetically deficient for TLR2-/-or TLR4-/-mice, displayed reduced intestinal inflammation. In these mice, the numbers of colonic ILC3s were significantly reduced, and the levels of IL-17 and IL-22 that can be secreted by ILC3s were also decreased in the colon tissues. Furthermore, HMGB1 promoted DCs via TLR2/4 signaling to produce IL-23, activating ILC3s to produce IL-17 and IL-22. Our data thus indicated that the HMGB1-TLR2/4-DCs-IL-23 cascade pathway enhances the functions of ILC3s to produce IL-17 and IL-22, and this signal way might play a vital role in the development of IBD.
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Xiangyu
X
Chen
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Lingyun
L
Li
2 Department of Immunology, Dalian Medical University, P. R. China.
Muhammad Noman
MN
Khan
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Lifeng
L
Shi
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Zhongyan
Z
Wang
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Fang
F
Zheng
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Feili
F
Gong
1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, P. R. China.
Min
M
Fang
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D000097043:Interleukin-22
D019138:Antibodies, Blocking; D024243:HMGB1 Protein; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000097043:Interleukin-22; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse
Inflammatory bowel disease; Toll-like receptor 2; Toll-like receptor 4; high-mobility group box 1; innate lymphoid cell