GABA-responsive neuronal regulation of TRPV1-mediated neuroinflammation in neurogenic rosacea

Summary: Abstract Body: Neurogenic rosacea is marked by vasodilation, telangiectasia, and flushing, with neurogenic inflammation central to its pathophysiology. Our previous study identified TRPV1 activation in DRG as a key driver of cutaneous neuroinflammation. While gabapentin (GBP) effectively alleviates neurogenic rosacea symptoms, its precise mechanism remains unclear. Hence, we investigated the neuroinflammatory pathways underlying rosacea using bulk RNA sequencing of skin and DRG from a rosacea mouse model. The data were analyzed through IPA and R programming, while protein analysis was conducted to validate the identified signaling pathways and GBP’s therapeutic role in alleviating vasodilation. RNA sequencing revealed upregulation of Th2 pathway in skin tissues and then TLR and Th2 pathways in DRG tissues, alongside activation of a vasodilation pathway associated with GABA signaling. Notably, the IGF pathway, related to neurogenic pain, was upregulated in DRG. In induced mice, CGRP levels were elevated in the skin compared to the control group, with increased expression near CD31-positive areas correlating with vasodilation, which was reduced following GBP administration. GBP reduced CGRP expression in the skin and CGRP/NF200 in DRG, demonstrating inhibition of peripheral vasodilation. This inhibitory mechanism was linked to GBP-induced downregulation of the NF-κB-eNOS/iNOS-VIP pathway in the skin. This study reveals novel signaling pathways in rosacea and demonstrates GBP's efficacy in modulating TRPV1-mediated neuroinflammation and vasodilation, highlighting its therapeutic potential in neurogenic rosacea and related conditions. Sang Gyu Lee^{1, 2}, Hyungsoon Im², Jinkee Hong³, Ju Hee Lee¹, Jihee Kim^{1, 4} 1. Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (the Republic of). 2. Center for Systems Biology, Massachusetts General Hospital, Boston, MA, United States. 3. Department of Chemical and Biomolecular Engineering, Yonsei University College of Engineering, Seoul, Korea (the Republic of). 4. Department of Dermatology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea (the Republic of). Translational Studies: Cell and Molecular Biology