MANF ameliorates DSS-induced mouse colitis via restricting Ly6ChiCX3CR1int macrophage transformation and suppressing CHOP-BATF2 signaling pathway
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Updated: Aug 14, 2025
Murine Colitis Modeling using Dextran Sulfate Sodium DSS
Published on: January 19, 2010
Lin Yang1,2, Wen-Wen Shen1,2, Wei Shao1,2
1School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
Abstract:
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 Ly6ChiCX3CRint 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.
Insights
Mesencephalic astrocyte-derived neurotrophic factor (MANF) negatively regulates inflammation in macrophages. MANF protects against inflammatory bowel disease (IBD) by reducing pro-inflammatory macrophages and associated cytokines.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum stress-inducible protein with immune-regulatory functions.
- MANF negatively regulates inflammation, particularly in macrophages.
Purpose of the Study:
- To investigate MANF profiles in macrophages from patients with active inflammatory bowel disease (IBD) and mice with experimental colitis.
- To determine the role of MANF in regulating inflammatory responses in IBD models.
Main Methods:
- Assessed MANF expression in intestinal macrophages from IBD patients and mice with dextran sodium sulfate (DSS)-induced colitis.
- Utilized myeloid cell-specific MANF knockout mice and wild-type mice.
- Administered recombinant human MANF (rhMANF) to DSS-treated mice.
- Analyzed macrophage populations (Ly6ChiCX3CRint) and cytokine/chemokine profiles.
Main Results:
- MANF expression was significantly increased in intestinal macrophages of both IBD patients and mice with experimental colitis.
- Myeloid cell-specific MANF knockout mice exhibited exacerbated DSS-induced colitis.
- rhMANF administration ameliorated experimental colitis.
- MANF deficiency led to increased proinflammatory macrophages and elevated cytokine/chemokine levels.
- MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11, and IL-12p40.
- MANF acts as a negative regulator in inflammatory macrophages via the CHOP-BATF2 signaling pathway.
Conclusions:
- MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation.
- MANF deficiency exacerbates colitis, while MANF administration shows therapeutic potential.
- MANF represents a potential therapeutic target for inflammatory bowel disease.
