Rethinking colitis: MrgprD puts macrophages in the driver's seat^†

There is increasing evidence to suggest that dysregulated macrophages play an important role in the promotion and maintenance of inflammatory bowel disease (IBD), yet the underlying mechanisms remain unclear. A recent study published by Lv, Xia, Qiao et al in The Journal of Pathology investigated the role of Mas-related G protein-coupled receptor D (MrgprD) as a surrogate for IBD using a dextran sulfate sodium-induced colitis mouse model. Through a series of experiments using Mrgprd knockout mice, the authors demonstrated that MrgprD drives colitis through its expression in macrophages, promoting M1 macrophage polarization via NF-κB signaling. They also showed that colitis was primarily driven by myeloid-specific rather than neuronal-specific MrgprdD expression. Finally, analysis of genomic data from patients with IBD supported the translational relevance of these findings to human disease. However, their findings require further verification. If confirmed, MrgprD could emerge as a promising treatment target. In any case, macrophages are receiving increasing attention, and pathologists may soon need to consider their assessment in their reporting. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.