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Updated: Jun 2, 2025
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8
Xianwen Ran1,2, Yue Li2,3, Yahui Ren4
1Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Abstract:
Macrophages play important roles in maintaining intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases (IBDs). However, the underlying mechanisms that govern macrophage-mediated inflammation are still largely unknown. In this study, we report that RNF128 is downregulated in proinflammatory macrophages. RNF128 deficiency leads to elevated levels of effector cytokines in vitro and accelerates the progression of IBD in mouse models. Bone marrow transplantation experiments revealed that RNF128 deficiency in bone marrow cells contributes to the worsening of DSS-induced colitis. Mechanistically, RNF128 interacts with and destabilizes S100A8 by promoting its autophagic degradation, which is mediated by the cargo receptor Tollip. Moreover, the administration of an S100A8 neutralizing antibody mitigated the development of colitis and improved survival in DSS-treated Rnf128-/- mice. Overall, our study underscores the anti-inflammatory role of RNF128 in macrophages during the progression of colitis and highlights the potential of targeting the RNF128-Tollip-S100A8 axis to attenuate intestinal inflammation for the treatment of colitis.
Insights
RNF128 is downregulated in inflammatory macrophages, worsening inflammatory bowel diseases (IBD). Restoring RNF128 function or targeting the RNF128-Tollip-S100A8 pathway may treat colitis.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Macrophages are crucial in intestinal homeostasis and inflammatory bowel diseases (IBDs).
- Mechanisms governing macrophage-driven inflammation in IBD remain incompletely understood.
- RNF128's role in macrophage function and intestinal inflammation is unexplored.
Purpose of the Study:
- To investigate the role of RNF128 in regulating macrophage activity and intestinal inflammation.
- To elucidate the molecular mechanisms by which RNF128 influences inflammatory responses.
- To evaluate the therapeutic potential of targeting the RNF128 pathway in colitis models.
Main Methods:
- Assessed RNF128 expression in proinflammatory macrophages.
- Utilized in vitro assays to measure cytokine levels in RNF128-deficient cells.
- Employed mouse models of IBD (DSS-induced colitis) and bone marrow transplantation.
- Investigated the interaction of RNF128 with S100A8 and Tollip using biochemical assays.
- Administered S100A8 neutralizing antibodies in mouse models.
Main Results:
- RNF128 expression is decreased in proinflammatory macrophages.
- RNF128 deficiency increases effector cytokine production and exacerbates IBD progression in mice.
- RNF128 deficiency in bone marrow cells worsens DSS-induced colitis.
- RNF128 promotes autophagic degradation of S100A8 via the cargo receptor Tollip.
- S100A8 antibody treatment ameliorates colitis and improves survival in Rnf128-deficient mice.
Conclusions:
- RNF128 acts as an anti-inflammatory factor in macrophages during colitis.
- The RNF128-Tollip-S100A8 axis is a key regulator of intestinal inflammation.
- Targeting this axis offers a potential therapeutic strategy for treating colitis and IBD.
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