RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8

Cell Death Dis. 2025 Jan 15;16(1):20. doi: 10.1038/s41419-025-07338-0.

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.

MeSH terms

  • Animals
  • Autophagy*
  • Calgranulin A* / genetics
  • Calgranulin A* / metabolism
  • Colitis* / chemically induced
  • Colitis* / metabolism
  • Colitis* / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Macrophages* / metabolism
  • Macrophages* / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Ubiquitin-Protein Ligases* / deficiency
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism

Substances

  • Calgranulin A
  • Ubiquitin-Protein Ligases
  • Dextran Sulfate
  • S100a8 protein, mouse