In the complex human gut ecosystem, white blood cells called macrophages play opposing yet complementary roles: some fight harmful microorganisms by triggering inflammatory reactions, while others repair damaged tissue and promote healing. When inflammatory cells predominate in this delicate balance, a process of chronic inflammation is triggered that characterizes Crohn’s disease, the best-known inflammatory bowel disease. A group of researchers from the University of California San Diego School of Medicine has now shed light on one of the most enduring mysteries in Crohn’s disease research. Their study finally explains how NOD2, the first gene associated with the risk of developing Crohn’s disease, identified in 2001, works. The answer was achieved combining artificial intelligence (AI) and advanced molecular biology.
The revolutionary aspect of the research lies in the use of machine learning algorithms to analyze thousands of gene expression profiles taken from both healthy colon tissue and tissue affected by inflammatory bowel disease. This computational analysis identified a genetic signature of 53 genes that reliably distinguish aggressive and inflammatory macrophages from those responsible for tissue repair. Among these 53 genes, one that encodes a protein called girdin/GIV stands out, proving to be the key player in this mechanism. In non-inflammatory macrophages, a specific portion of the NOD2 protein binds to girdin, creating a molecular alliance that keeps inflammation under control, eliminates pathogenic bacteria, and allows tissue regeneration.
The problem arises with the most common NOD2 mutation associated with Crohn’s disease: this alteration eliminates the very section where girdin normally attaches, breaking the protective bond. Mechanistically, the C-terminus of GIV binds to the terminal leucine-rich repeat (LRR10) of NOD2 and is required for NOD2 to dampen inflammation and eliminate microbes. Through cross-scale analyses integrating computational transcriptomics, proteomics, and in vivo interventional studies, the researchers identified girdin/GIV as a key regulator of repairing macrophages, dubbed non-inflammatory colon-associated macrophages (NICAMs). GIV emerged as the top-ranking gene in NICAMs that physically and functionally interacts with NOD2, an innate immune sensor also implicated in celiac disease.
Myeloid bone marrow-specific GIV depletion exacerbates infectious colitis, prolongs disease, and abrogates the protective effects of the NOD2 ligand, muramyl dipeptide, in models of colitis and sepsis. To validate their findings, the researchers conducted experiments on mouse models of Crohn’s disease, comparing mice lacking GIV with mice that normally possess it. The results were dramatic: animals lacking girdin developed severe intestinal inflammation and microbiota alterations, and many died from sepsis. In the match between “warrior” macrophages and “peacekeepers,” AI was able to assign an identification tag to the two teams, which is a feat, since in other pathological conditions involving multiple cell types, the same approach could identify the cells that initiate the pathological process and those that shut it down.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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