Regional macrophage specialization shapes intestinal neuroimmune function

Tissue-resident macrophages adapt to local environments to support organ-specific functions, but whether their regulation differs across regions of the same organ is poorly understood. The gastrointestinal tract provides an ideal system to address this question because its anatomically distinct regions perform specialized physiological functions and contain different cellular environments. Here, we found that intestinal muscularis macrophages (MMs) exhibited distinct regional trophic requirements and neuroimmune functions across the gut. Small-intestinal MMs were highly sensitive to CSF1 neutralization but recovered robustly, whereas colonic MMs were less sensitive to CSF1 depletion yet showed limited recovery. Disruption of CSF1-dependent MMs selectively reduced nitrergic neurons and altered motility in the small intestine, whereas the colonic neuronal compartment was comparatively preserved. Csf1 was enriched in small-intestinal nNOS ⁺ neurons, and neuron-specific Csf1 deletion reduced both MMs and nitrergic neurons and altered small-intestinal transit, with limited effects in the colon. Together, these findings reveal that macrophage trophic requirements and neuroimmune functions are regionally specialized within the intestine and identify neuronal CSF1 as a key component of the trophic relationship between nitrergic neurons and MMs in the small intestine.