Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice
Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang
Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang
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Research Article Immunology Inflammation

Lactobacillus rhamnosus GG induces STING-dependent IL-10 in intestinal monocytes and alleviates inflammatory colitis in mice

Abstract

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10–based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade–associated colitis. Our findings highlight the importance of STING signaling in IL-10–dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Authors

Wei Si, Xin Zhao, Ruitong Li, Yaopeng Li, Cui Ma, Xiaohan Zhao, Jason Bugno, Yuchang Qin, Junmin Zhang, Hongwei Liu, Liangliang Wang

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Figure 5

LGG triggers an IL-10–based autocrine regulatory loop in monocytes during colitis.

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LGG triggers an IL-10–based autocrine regulatory loop in monocytes durin...
(A) Percentages of IL-10R+ immune cells in MLNs from WT mice with the indicated treatment (n = 5 per group). (B) Ly6C+ monocytes were isolated from MLNs in WT mice with different treatments as indicated and subjected to qPCR analysis of the mRNA levels of Tnfa, Il6, and Il1b (n = 3 per group). (C) Ly6C+ monocytes were isolated from LGG+DSS-treated mice and stimulated with recombinant IL-10 (10 ng/mL) for 60 minutes. The supernatant was collected to detect the protein levels of inflammatory cytokines using a LEGENDplex cytokine kit (n = 5 per group). (D) CD45.1 monocytes (WT or Il10r knockdown) were sorted after coculture with CD45.2 monocytes from MLNs of DSS- or LGG+DSS-treated mice and subjected to qPCR analysis of the mRNA levels of Tnfa, Il6, and Il1b (n = 5 per group). (E) qPCR analysis of monocytes (as indicated in D) in the presence of a neutralizing anti–IL-10R antibody (10 μg/mL) (n = 5 per group). Data are expressed as mean ± SEM. One of 2 or 3 representative experiments is shown. Statistical analysis was performed using 1-way ANOVA with Bonferroni’s multiple comparison tests (A and B) and unpaired 2-tailed Student’s t tests (C–E). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.