Monocytes Mobilized by Gut Neurons Remodel the Enteric Nervous System

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Monocytes Mobilized by Gut Neurons Remodel the Enteric Nervous System

Authors

Kurapati, S.; Shin, C.; Szabo, K.; Liu, Y.; Ashraf, A.; Koscso, B.; Dash, C.; Navarro, L.; Saha, M.; Nagaraj, S.; Wang, W.; Zhu, J.; Shulzhenko, N.; Baer, C.; Srinivasan, S.; Kulkarni, S.; Pasricha, P.; Peters, L.; Bogunovic, M.

Abstract

The proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) dysregulates GI physiology, including bowel movements (motility), but in many IBD patients, GI motility disorders persist in remission through a poorly understood pathological process. Here we uncover that post-inflammatory GI dysmotility (PI-GID) stems from structural ENS remodeling driven by a combination of neuronal loss and neurogenesis. Enteric neurons respond to mucosal inflammation by upregulating CCL2 expression and facilitating the recruitment of CCR2+ monocytes into the neural myenteric plexus within the intestinal muscle. This is followed by the expansion of monocyte-derived macrophages and their migration into the myenteric ganglia and phagocytosis of neurons. However, excessive recruitment of monocytes results in disproportionate ENS remodeling and PI-GID. The expansion of inflammatory cells is known to promote tissue hypoxia. We find that enteric neurons become hypoxic upon colitis, but hypoxia-induced signaling via HIF1a; initiates an adaptation program in enteric neurons to attenuate CCL2 expression and limit monocyte recruitment. We demonstrate that reinforcing HIF1a; signaling in enteric neurons prevents PI-GID by reducing colitis-associated monocyte recruitment in the myenteric plexus and protecting against ENS remodeling. In summary, our findings unveil PI-GID pathogenesis and identify a regulatory axis for its prevention.

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