Contributions of itch-sensing neurons to skin anti-helminth immunity - Project Summary Skin-penetrating helminths affect 1.5 billion people worldwide and can cause clinically significant itch. However, whether itch-inducing neurons regulate skin anti-helminth immunity is unknown. Cutaneous infections with the helminth Schistosoma mansoni cause mild itch and little skin irritation that result in parasite dissemination. My recently published studies demonstrate that S. mansoni suppresses itch evoked by neurons bearing the Mas- related G protein-coupled receptor (Mrgpr) A3. However, the molecular mechanisms by which S. mansoni inhibits MrgprA3 neurons are undefined. My published studies also showed that activation of MrgprA3 neurons induced IL-17-mediated inflammation, keratinocyte thickening, and skin resistance to S. mansoni dependent on antigen- presenting cells. However, the effector mechanisms by which MrgprA3 neurons induce skin inflammation and anti-parasitic immunity are obscure. Two main subsets of itch-transmitting neurons are defined by MrgprA3 (NP2) and MrgprD (NP1) in mice, but these two neuronal subsets express remarkably distinct transcriptional programs and have unique functions. In contrast to the pro-inflammatory properties of MrgprA3 neurons, my preliminary data show that MrgprD neuron stimulation limits IL-17-driven skin inflammation and promotes secretion of the anti-inflammatory cytokine IL-10, which is well-known to promote S. mansoni systemic dissemination. Based on these studies, this K99/R00 proposal is designed to test the central hypothesis that S. mansoni inhibits MrgprA3 neurons that initiate IL-17-driven keratinocyte responses but preferentially stimulates MrgprD neurons that suppress skin immunity by inducing IL-10 secretion. This hypothesis will be tested in three specific but complementary aims. Aim 1 (K99) will determine how S. mansoni blocks the activation and itch evoked by MrgprA3 neurons. Aim 2 (K99/R00) will test if MrgprA3 neurons protect against S. mansoni by eliciting IL-17- dependent keratinocyte proliferation and maturation. The R00 independent phase in Aim 3 will leverage the expertise acquired in Aim 1 and 2 to define if S. mansoni directly activates MrgprD neurons to promote IL-10- dependent immunosuppression that facilitates its dissemination. The studies of this K99/R00 proposal may inform new therapies against chronic itch and skin helminth infections. The principal investigator (PI), Dr. Juan Inclan-Rico, will learn the skills and techniques necessary to accomplish the proposed research under the guidance of his mentoring team, led by Drs. Wenqin Luo and De’Broski Herbert, who have pioneering expertise in somatosensation and immunoparasitology. Collectively, the mentoring committee has a proven record of transitioning postdoctoral fellows into independent investigators. Dr. Inclan-Rico will also acquire the leadership, management, mentorship, and grantsmanship skillset necessary to run his own laboratory. The PI’s strong enthusiasm, publication record, and commitment to science, combined with the training obtained during the K99 mentored phase, will define a clear path to establish his independent research program that defines the contributions of itch-inducing neurons to skin immunity during infectious and non-infectious conditions.
