Regional macrophage specialization shapes intestinal neuroimmune function
- 1Enteric Neuroscience Program (ENSP), Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Abstract
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.
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BibTeX
@misc{warasnhe2026regional,
title = {{Regional macrophage specialization shapes intestinal neuroimmune function}},
author = {K. Warasnhe and J. S. Ortiz Colmenares and M. D'Ambrosio and B. Di Lorenzo and Y. Liu and S. Ji and M. Mischopoulou and N. R. Wertish and M. H. Eldesouki and X.-y. Chai and J. X. Jiang and M. Grover and K. A. Sharkey and A. Beyder and G. Farrugia and G. Cipriani},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757647},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757647v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Regional macrophage specialization shapes intestinal neuroimmune function
AU - K. Warasnhe
AU - J. S. Ortiz Colmenares
AU - M. D'Ambrosio
AU - B. Di Lorenzo
AU - Y. Liu
AU - S. Ji
AU - M. Mischopoulou
AU - N. R. Wertish
AU - M. H. Eldesouki
AU - X.-y. Chai
AU - J. X. Jiang
AU - M. Grover
AU - K. A. Sharkey
AU - A. Beyder
AU - G. Farrugia
AU - G. Cipriani
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757647
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757647v1
AB - 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.
ER -