Adrenergic signaling in muscularis macrophages limits neuronal death following enteric infection

Abstract

Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility. Bidirectional interactions between immune and neuronal cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated how infection-induced inflammation affects intrinsic EANs and the role of intestinal muscularis macrophages (MMs) in this process. Using murine model of bacterial infection, we observed long-term gastrointestinal symptoms including reduced motility and subtype-specific neuronal loss. Neuronal-specific translational-profiling uncovered a caspase 11-dependent EAN cell-death mechanism induced by enteric infections. MMs responded to luminal infection by upregulating a neuroprotective program; gain- and loss-of-function experiments indicated that {beta}2-adrenergic receptor ({beta}2-AR) signaling in MMs mediates neuronal protection during infection via an arginase 1-polyamine axis. Our results identify a mechanism of neuronal cell death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.