Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cellsopen access
- Authors
- Mishima, Yoshiyuki; Oka, Akihiko; Liu, Bo; Herzog, Jeremy W.; Eun, Chang Soo; Fan, Ting-Jia; Bulik-Sullivan, Emily; Carroll, Ian M.; Hansen, Jonathan J.; Chen, Liang; Wilson, Justin E.; Fisher, Nancy C.; Ting, Jenny P. Y.; Nochi, Tomonori; Wahl, Angela; Garcia, J. Victor; Karp, Christopher L.; Sartor, R. Balfour
- Issue Date
- Sep-2019
- Publisher
- AMER SOC CLINICAL INVESTIGATION INC
- Citation
- JOURNAL OF CLINICAL INVESTIGATION, v.129, no.9, pp.3702 - 3716
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF CLINICAL INVESTIGATION
- Volume
- 129
- Number
- 9
- Start Page
- 3702
- End Page
- 3716
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/13203
- DOI
- 10.1172/JCI93820
- ISSN
- 0021-9738
- Abstract
- Resident microbiota activates regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies describe the functional importance and mechanisms by which gut microbiota and specific microbial components influence the development of intestinal IL-10-producing B cells. Using fecal transplant into germ-free (GF) Il10(+/EGFP) reporter and Il10(-/-) mice, we demonstrated that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory 1 cells in ex-GF mice. IL-10 in turn downregulated microbiota-activated mucosal inflammatory cytokines. TLR2 and -9 ligands and enteric bacterial lysates preferentially induced IL-10 production and the regulatory capacity of intestinal B cells. Analysis of Il10(+/EGFP) mice crossed with additional gene-deficient strains and B cell cotransfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2-, MyD88-, and PI3K-dependent fashion. In vitro studies implicated downstream signaling of PI3Kp110 delta and AKT. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88, and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.
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