Adrenergic Signaling in Muscularis Macrophages Limits Infection-Induced Neuronal Loss

Highlights

• Enteric pathogens trigger reversible neuronal loss and long-term GI symptoms

• Enteric infection-triggered neuronal loss is Nlrp6- and caspase 11-dependent

• Intestinal muscularis macrophages (MMs) rapidly respond to enteric pathogens

• Neuronal death is limited by a MM-β₂-adrenergic-arginase 1-polyamine axis

Summary

Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal muscularis macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a Nlrp6- and Casp11-dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via β₂-adrenergic receptor (β₂-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.