Sensory neuronal regulation of intestinal inflammation and immunity 2238700

Abstract Introduction Pain is a hallmark of infection and inflammation, but the role of pain-sensing nociceptors in tissue immunity is poorly defined. We previously showed that gut-innervating TRPV1+ nociceptors shape the intestinal microbiota to promote protection upon acute injury (Zhang et al., Cell 2022), highlighting their immunoregulatory function. At barrier surfaces, type 2 inflammation is an evolutionarily conserved response driving parasite defense, allergy, and repair, initiated by epithelial and immune sensing and further modulated by neuronal signals. How these diverse inputs are coordinated and integrated, however, is poorly understood. Methods In this study, we utilize mouse chemogenetics, scRNA sequencing, spatial transcriptomics, 3D tissue imaging and computational analyses to interrogate the functional interactions between sensory neurons, chemosensory tuft cells and anti-helminth type 2 immune responses. Results We demonstrated that TRPV1+ nociceptors co-opt chemosensory tuft cells to orchestrate protective anti-helminth type 2 immunity. Chemogenetic silencing of TRPV1+ nociceptors resulted in significantly reduced intestinal tuft cells and defective anti-helminth type 2 immunity. Conversely, chemogenetic activation of TRPV1+ nociceptors lead to enhanced intestinal CGRP+ innervation, increased tuft cell accumulation and protective anti-helminth type 2 immunity. Spatial transcriptomic analysis revealed nociceptor activation stimulated rapid epithelial progenitor proliferation and differentiation associated with tuft cell accumulation. Mechanistically, intestinal epithelial cell-intrinsic expression of CGRP receptors were required for anti-helminth type 2 immunity. Conclusion These findings identify a previously unrecognized neuronal—tuft cell circuit as a key upstream regulator of mucosal type 2 immunity (Zhang et al., Nature, accepted), establishing a new paradigm in which peripheral sensory neurons and chemosensory epithelial cells converge to initiate protective immunity at barrier surfaces. Funding Source 2024 NIDDK K99/R00 Transitional to Independence Award, 2024 MIST Scholar Award, Allen Discovery Center program Topic Categories Mucosal and Regional Immunology (MUC)