Targeting cutaneous nociceptors to reduce Type-17 inflammation in hidradenitis suppurativa

This application, Targeting cutaneous nociceptors to reduce Type-17 inflammation in Hidradenitis Suppurativa, is submitted by me, Sarah Whitley, MD, PhD, in the University of Pittsburgh Department of Dermatology for a Mentored Clinician Scientist Career Development Award (K08). I have a strong background in T helper 17 (Th17) biology and a commitment to research in cutaneous immunology. To complete my research objectives, I will gain and extend expertise in clinical/translational research, computational biology, neurobiology, and the clinical care of patients afflicted by the devastating and poorly understood skin disease Hidradenitis Suppurativa (HS). I present preliminary data showing that isolated activation of cutaneous TRPV1-nociceptors, which transduce pain signals through unmyelinated sensory afferents, is sufficient to induce expression of IL-1, IL-6, TNF, and IL-23 and expand IL-17-producing CD4+ T cells in skin. I show that the TRPV1+-nerve-derived neuropeptides CGRP and Substance P (SP) enhance human skin dendritic cell (DC) responsiveness to toll-like receptor stimulation. Finally, I demonstrate that blockade of neuropeptide release with botulinum toxin reduces T cell density in the skin of HS patients to improve disease control. In Aim 1, I propose to more precisely characterize the immune cells infiltrating the pilosebaceous unit in HS skin using a highly innovative spatial transcriptomic technology. Aim 2 will test the hypothesis that inhibiting neuropeptide activity with botulinum toxin reduces IL-17 and TNF production in skin. Aim 3 will evaluate the functional outcome of SP and CGRP signaling in skin using in vitro assays and single cell RNA-sequencing analyses of HS skin explants treated with neuropeptide or vehicle. Together, these aims will test our central hypothesis that neurogenic inflammation heightens cDC2 sensitivity to microbial products to induce aberrant Type-17 inflammation. It is our expectation that these experiments will implicate neurogenic inflammation in the pathogenesis of HS and serve as proof-of-concept for clinical trials evaluating the efficacy of nociceptor inhibition in reduction of inflammation, relief of pain, and improvement in quality of life for HS patients. My work will proceed under close advisement from my primary mentor, Dr. Daniel Kaplan, co-mentor Dr. Robert Lafyatis, and scientific advisors with expertise in areas that fill key gaps in my previous training. I have an environment of enduring support from my mentors, department, and institution which has nationally recognized strength in translational research. With support from this mentored award, these studies will yield the preliminary data needed for a competitive R01 application and successfully launch an independent career.