Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

Department of Biological Sciences Zuckerman Mind Brain Behavior Institute Columbia University New York NY USA

Department of Neuroscience School of Medicine University of Pennsylvania Philadelphia PA USA

Department of Parasitology Faculty of Science Charles University Prague Czech Republic

Department of Pathobiology School of Veterinary Medicine University of Pennsylvania Philadelphia PA USA

Institute for Regenerative Medicine School of Medicine University of Pennsylvania Philadelphia PA USA

Monell Chemical Senses Center Philadelphia PA USA

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Res Sq. 2023 Nov 30:rs.3.rs-3644984. doi: 10.21203/rs.3.rs-3644984/v1. PubMed

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