2025-10-27 カリフォルニア大学サンディエゴ校(UCSD)
Electron micrographs show how macrophages expressing girdin neutralize pathogens by fusing phagosomes (P) with the cell’s lysosomes (L) to form phagolysosomes (PL), compartments where pathogens and cellular debris are broken down (left). This process is crucial for maintaining cellular homeostasis. In the absence of girdin, this fusion fails, allowing pathogens to evade degradation and escape neutralization (right). (UC San Diego Health Sciences)
<関連情報>
- https://today.ucsd.edu/story/rebalancing-the-gut-how-ai-solved-a-25-year-crohns-disease-mystery
- https://www.jci.org/articles/view/190851
異なる大腸炎関連マクロファージがNOD2依存性細菌感知と腸管恒常性維持を促進する Distinct colitis-associated macrophages drive NOD2-dependent bacterial sensing and gut homeostasis
Gajanan D. Katkar, Mahitha Shree Anandachar, Stella-Rita C. Ibeawuchi, Ella G. McLaren, Megan L. Estanol, Kennith Carpio-Perkins, Shu-Ting Hsu, Celia R. Espinoza, Jane E. Coates, Yashaswat S. Malhotra, Madhubanti Mullick, Vanessa Castillo, Daniella Vo, Saptarshi Sinha, and Pradipta Ghosh
Journal of Clinical Investigation Published: October 2, 2025
DOI:https://doi.org/10.1172/JCI190851
Abstract
Single-cell studies have revealed that intestinal macrophages maintain gut homeostasis through the balanced actions of reactive (inflammatory) and tolerant (non-inflammatory) subpopulations. How such balance is impaired in inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of non-inflammatory colon-associated macrophages (niColAMs) in IBD recovery. Through trans-scale analyses—integrating computational transcriptomics, proteomics, and in vivo interventional studies—we identified GIV (CCDC88A) as a key regulator of niColAMs. GIV emerged as the top-ranked gene in niColAMs that physically and functionally interacts with NOD2, an innate immune sensor implicated in CD and UC. Myeloid-specific GIV depletion exacerbates infectious colitis, prolongs disease, and abolishes the protective effects of the NOD2 ligand, muramyl dipeptide, in colitis and sepsis models. Mechanistically, GIV’s C-terminus binds the terminal leucine-rich repeat (LRR#10) of NOD2 and is required for NOD2 to dampen inflammation and clear microbes. The CD-associated 1007fs NOD2-variant, which lacks LRR#10, cannot bind GIV—providing critical insights into how this clinically relevant variant impairs microbial sensing and clearance. These findings illuminate a critical GIV-NOD2 axis essential for gut homeostasis and highlight its disruption as a driver of dysbiosis and inflammation in IBD.
