Adrenergic signaling in muscularis macrophages limits infection-induced neuronal loss

Enteric–associated neurons (EAN) 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 EAN (iEAN) and the role of intestinal muscularis macrophages (MM) in this process. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms including reduced motility and loss of excitatory iEAN, which was mediated by an NLRP6 and caspase 11 mechanism, depended on infection history, and could be reversed by microbiota manipulation. MM responded to luminal infection by upregulating a neuroprotective program dependent on β2-adrenergic receptor (β2-AR) signaling, and mediated neuronal protection 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 MM in limiting neuronal damage. Actively translated mRNA profiles from immunoprecipitated ribosome-bound mRNA from the ileum muscularis and nodose ganglion of Snap25:RiboTag mice were prepared by deep sequencing on an Illumina NextSeq Actively translated mRNA profiles from immunoprecipitated ribosome-bound or input mRNA from the ileum muscularis of LysM:Adrb2floxflox:RiboTag or LysM:Adrb2floxplus:RiboTag mice were prepared by deep sequencing on an Illumina NextSeq