Neuroimmune Control of Microbiota-Evoked Hyperinnervation and Pruritus

About This Grant

PROJECT SUMMARY/ABSTRACT My goal is to understand the mechanisms underlying pruritus. The ability to sense the environment is essential for survival, with the somatosensory nervous system playing a central role in detecting external stimuli. Despite its evolutionary relevance, the sensation of itch (pruritus) has been historically overlooked, even though it significantly impacts quality of life, particularly in chronic cases. Of note, pruritus affects 15% of the population, yet there are very few FDA-approved treatments, making it a major unmet medical need. Recent studies highlight the crucial interactions between the immune and sensory systems, especially the role of unmyelinated C-fibers in driving both inflammation and pruritus. While C-fiber hyperinnervation is a feature of pruritus, the mechanisms driving this nerve overgrowth and its role in pruritus pathogenesis remain largely unknown. The skin is the primary sensory organ for pruritus and the ecological niche for commensal microbiota. Using a novel TCR transgenic mouse model with T cells specific for Staphylococcus aureus (S. aureus), I previously demonstrated that T cell immunity to commensal S. aureus promotes skin sensory nerve regrowth after injury via the IL- 17A/IL-17RA axis. While host-microbiota interactions are essential for maintaining immune balance and skin homeostasis, disruption of this equilibrium can transform commensals such as S. aureus into pathogenic drivers of inflammation and tissue damage, as observed in psoriasis and atopic dermatitis. Might microbiota- induced cytokines contribute to these outcomes? Building on the neurotrophic effect of microbiota-induced IL- 17A, and considering the established role of type 2 cytokines (IL-3, IL-4, IL-13, IL-31) in itch via sensory nerve activation, my lab is investigating whether IL-17A promotes maladaptive neuronal growth during inflammation, leading to sensory hyperinnervation and pruritus. To test this, we have used two models of skin microbiota (S. aureus and Candida albicans) combined with two inflammatory itch models: IMQ-induced psoriatic itch and MC903-induced atopic dermatitis. We have found that mice in the pruritus group (microbiota + IMQ/MC903) showed both skin hyperinnervation and heightened itch, driven by the IL-17A/IL-17RA axis. Furthermore, snRNA-seq of dorsal root ganglia (DRG) neurons and microscopy revealed a transcriptional signature consistent with axonal growth, including upregulation of Atf3, a key regulator of nerve growth following injury Based on this, I hypothesize that microbiota-induced T cells control skin sensory hyperinnervation upon inflammation, consequently regulating pruritus via the ATF3-IL-17RA axis. To test this hypothesis, I will ask three interrelated but non-dependent aims: Aim 1) How do microbiota-induced T cells control hyperinnervation, Aim 2) To elucidate the transcriptional regulation of IL-17RA- dependent sensory hyperinnervation, and Aim 3) How does ATF3-IL-17RA axis regulate pruritus? This project seeks to establish a novel paradigm of microbiota-driven neuroimmune regulation of sensory neuron plasticity, focusing on hyperinnervation, and long-term effects on pruritus, very relevant to target inflammatory skin conditions.