Activated MrgprD+ neurons shift γδ T cell responses and suppress imiquimod-induced dermatitis 2256517

Introduction Psoriasis is a chronic autoimmune skin disorder marked by excessive IL-17-driven inflammation and pruritus. Although intense itching is a key disease feature, the contribution of specific subsets of itch-inducing neurons to skin immunopathology is unknown. Methods This study employed a mouse model of psoriatic-like pathology induced by topical application of imiquimod (IMQ) to investigate the role of type 1 non-peptidergic (NP1) afferents bearing the Mas-related G protein-coupled receptor D (MrgprD). Results Although IMQ application reduced the epidermal density of MrgprD+ skin afferents, optogenetic or pharmacological activation of NP1 neurons before IMQ exposure significantly ameliorated epidermal thickness and psoriasiform clinical score. Conversely, ablation of MrgprD+ afferents resulted in increased skin inflammation after eight days of IMQ application. Data show that optogenetic or pharmacologic stimulation of NP1 neurons attenuated neutrophil skin influx, IL-17 cytokine responses, and γδ T cell accumulation in skin-draining lymph nodes (sdLN). Pre-emptive stimulation of NP1 neurons reduced γδ T cell-derived IL-17 and amphiregulin (Areg), but increased secretion of the immunosuppressive cytokine IL-10, and elevated γδ T cells expressing IL-13 and the transcription factor GATA3. Conclusion These data support a model wherein NP1 afferents that promote immunoregulatory responses by modulating γδ T cells are lost in the context of psoriatic inflammation. Funding Source National Institutes of Health (grant no. 1K99AI187730-01A1)