Type 2 cytokines act on enteric sensory neurons to regulate neuropeptide-driven host defense [scRNA-Seq]

Enteric nervous system (ENS)-derived neuropeptides modulate immune cell function, yet our understanding of how inflammatory cues directly influence enteric neuron responses during infection is considerably lacking. Here, we characterize a primary enteric sensory neuron (PSN) subset that produces the neuropeptides neuromedin U (NMU) and calcitonin gene-related peptide beta (CGRPβ) and co-expresses receptors for the type 2 cytokines IL-4 and IL-13. Type 2 cytokines were sufficient to upregulate NMU and CGRPβ expression in PSNs, in vitro and in vivo, which was abrogated by PSN-specific Il13ra1 deletion. Importantly, PSN-specific Il13ra1 deletion impaired host defense to the gastrointestinal helminth H. polygyrus, diminished enteric sensory neuron populations, and blunted muscularis immune responses. Co-administration of NMU23 and CGRPβ rescued helminth clearance deficits and restored anti-helminth immunity. Mechanistically, we show that CGRPβ signaling synergizes with IL-4 in intestinal macrophages, inducing alternatively-activated macrophage defense responses, altogether illustrating the critical role of bi-directional neuro-immune crosstalk in regulating intestinal type 2 immunity.