Dissecting the role of sensory neurons in response to skin parasites

Summary: Abstract Body: The skin is a vital interface critical in maintaining commensal microorganisms while defending from pathogenic ones. Sensory neurons have been implicated in coordinating immune responses against microbes, but their role in response to parasitic infections remains unclear. In this study, we use the Demodex infection model, a commensal parasite that inhabits mammalian hair follicles, to dissect how this parasite may influence the nervous system. We hypothesized that sensory neurons influence the immune response to Demodex infection by increasing the expression of neuropeptides. We performed bulk RNA sequencing of trigeminal ganglia, which revealed minimal transcriptional changes during early infection despite increased expression of the neuropeptide Calca in the trigeminal ganglia and skin over time. Pharmacological sensory denervation with resiniferatoxin (RTX) or genetic denervation using Trpv1-Cre; R26DTA mice led to modest changes in ILC2 populations. RNA sequencing analysis of the skin identified upregulation of gasdermin C (GsdmC) family proteins and IL-36 cytokines in Demodex-infected skin, implicating increased keratinocyte-mediated inflammation in response to mite colonization. Type 2 immunodeficient mice (Il4–/–/Il13–/– or Il4ra–/–), which cannot control Demodex infection, exhibited heightened inflammatory and neuropeptide responses to Demodex, which were mitigated by antiparasitic treatment. Our data highlight potential crosstalk between sensory neurons and keratinocytes in orchestrating localized immune responses to skin-dwelling parasites. These findings suggest that Demodex mites may interact with the sensory neurons to regulate inflammation in a controlled, non-pathologic fashion. This work can help uncover mechanisms underlying neurogenic inflammation in inflammatory skin diseases, offering potential avenues for developing targeted therapies for conditions like atopic dermatitis. Tithi Roy¹, Elizabeth Arouge¹, Lena Tama¹, Mi Lian², Anusha Subramanian¹, Steven Lazarevsky¹, Richard M. Locksley², Marlys Fassett¹, Roberto R. Ricardo-Gonzalez^{1, 3} 1. Dermatology, University of California San Francisco, San Francisco, CA, United States. 2. Medicine, University of California San Francisco, San Francisco, CA, United States. 3. Chan Zuckerberg Biohub, San Francisco, CA, United States. Innate Immunity, Microbiology, and Microbiome