Blocking the m⁶Am methyltransferase PCIF1 in macrophages attenuates colitis progression by preventing neuronal damage

Macrophage-enteric neuron dialog is crucial for intestinal homeostasis, but its specific role and underlying mechanism in inflammatory bowel disease (IBD) pathogenesis remain elusive. Here, we demonstrate that colonic macrophage-mediated extracellular matrix (ECM) remodeling orchestrates enteric neuronal maturation and dictates colitis progression. The depletion of Pcif1, recognized as a unique methyltransferase for m⁶Am mRNA methylation, in macrophages attenuates colitis and protects enteric neurons from inflammation-driven degeneration. Specifically, Pcif1-deficient macrophages increase ECM accumulation, promoting their own extravasation into enteric neuronal plexuses and the maturation of enteric neurons, thereby curbing inflammation-driven neuronal injury and colitis progression. Mechanistically, Pcif1-mediated m⁶Am modification inhibits the translation of Znf219 mRNA and represses the Znf219-Egr1 axis, a master transcriptional module that governs ECM remodeling. Finally, pharmacological blockade of PCIF1 promotes macrophage-mediated ECM deposition and suppresses colitis and neuronal loss. Our findings reveal a novel mechanism whereby ECM remodeling in macrophages drives enteric neuronal maturation and illuminate the m⁶Am machinery as a promising therapeutic target for preventing neuronal loss in IBD patients.