MANF ameliorates DSS-induced mouse colitis via restricting Ly6ChiCX3CR1int macrophage transformation and suppressing CHOP-BATF2 signaling pathway

Lin Yang1,2, Wen-wen Shen1,2, Wei Shao1,2, Qing Zhao1,2, Gao-zong Pang1,2, Yi Yang1,2,3, Xiao-fang Tao1,2, Wei-ping Zhang3, Qiong Mei1,2, Yu-xian Shen1,2
1 School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
2 Biopharmaceutical Institute, Anhui Medical University, Hefei 230032, China
3 First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
Correspondence to: Yu-xian Shen:,
DOI: 10.1038/s41401-022-01045-8
Received: 28 August 2022
Accepted: 19 December 2022
Advance online: 12 January 2023


Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible secreting protein, has evolutionarily conserved immune-regulatory function that contributes to the negative regulation of inflammation in macrophages. In this study, we investigated the profiles of MANF in the macrophages of the patients with active inflammatory bowel disease (IBD) and the mice with experimental colitis, which was induced in both myeloid cell-specific MANF knockout mice and wild-type mice by 3% dextran sodium sulfate (DSS) for 7 days. We found that MANF expression was significantly increased in intestinal macrophages from both the mice with experimental colitis and patients with active IBD. DSS-induced colitis was exacerbated in myeloid cell-specific MANF knockout mice. Injection of recombinant human MANF (rhMANF, 10 mg·kg–1·d–1, i.v.) from D4 to D6 significantly ameliorated experimental colitis in DSS-treated mice. More importantly, MANF deficiency in myeloid cells resulted in a dramatic increase in the number of Ly6ChiCX3CR1int proinflammatory macrophages in colon lamina propria of DSS-treated mice, and the proinflammatory cytokines and chemokines were upregulated as well. Meanwhile, we demonstrated that MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11 and IL-12p40; MANF functioned as a negative regulator in inflammatory macrophages via inhibiting CHOP-BATF2 signaling pathway, thereby protecting against DSS-induced mouse colitis. These results suggest that MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation, which shed light on a potential therapeutic target for IBD.
Keywords: inflammatory bowel disease; colitis; MANF; macrophages; Th17 cells; BATF2-mediated innate immune response; CHOP- BATF2 signaling

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