“Listen to your nerves”: Skin Sensory Neurons promote Immunity against Parasitic Worms 2266688

Abstract Introduction Skin employs interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. While bacteria and fungi often cause painful and itchy cutaneous reactions, host skin invasion by the human parasitic helminth Schistosoma mansoni frequently goes unnoticed. Methods Our studies interrogated whether sensory neurons that transmit itch and pain contributed to the detection and initiation of skin immunity against S. mansoni. Results Herein, we demonstrate that S. mansoni exposure inhibited itch evoked by afferents bearing the MrgprA3 receptor in mice. In vitro approaches revealed that S. mansoni was directly recognized by MrgprA3+ neurons, but this interaction prevented calcium influx and neuropeptide release induced by the MrgprA3 ligand chloroquine. S. mansoni infection also significantly reduced thermal pain sensitivity evoked by TRPV1+ neurons and neuropeptide release induced by the TRPV1 agonist capsaicin. Data show that MrgprA3+ or TRPV1+ neurons promoted IL-17+ gd T cell expansion and host resistance against S. mansoni through shaping cytokine expression in cutaneous macrophages. MrgprA3+ neuron secretions increased chromatin accessibility and expression of inflammatory cytokines in macrophages, partially through the neuropeptide CGRP. Conclusion Taken together, this work suggests that S. mansoni may have evolved to manipulate MrgprA3+ or TRPV1+ neuron activation as a countermeasure to limit IL-17-mediated inflammation, facilitating systemic dissemination and chronic parasitism. We will define the mechanisms underlying these interactions in my independent research program that will define the contributions of itch-inducing neurons to skin anti-helminth immunity. Funding Source NIH-NIAID Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)