Xueping Zhu, Haibo Yang, Haoting Zhan, Isabela J Kernin, Dean R Buttaci, Ngoc Le, Cai Han, Parth R Naik, Peri R Matatia, Sarah Zaghouani, Lillian R Delacruz, Lukas M Altenburger, Neal P Smith, Elena Wu, Rebecca Londoner, Cameron H Flayer, Zhengwang Sun, Alison E Ringel, Alexandra-Chloe Villani, Rod A Rahimi, Caroline L Sokol
Environmental allergens are enriched in protease activity, which activates cutaneous sensory neurons, triggering itch and substance P release to promote migration of T helper (Th)2 cell-skewing CD301b+ dendritic cells and initiate allergic immunity. However, allergens are typically encountered through repeated subthreshold exposures, and how these cumulatively induce sensitization is unknown. We identified a sensory neuron-intrinsic mechanism of neuroimmune memory. Protease allergen exposure induced sustained mechanistic target of rapamycin complex 1 (mTORC1) kinase signaling and transcriptional activator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-associated mitochondrial remodeling in sensory neurons, establishing a metabolically primed state with enhanced neuronal responsiveness. Upon allergen re-exposure, this state drove enhanced itch, CD301b+ dendritic cell migration, and Th2 cell differentiation. Disrupting neuronal mTORC1 signaling or mitochondrial stability abrogated this amplification while sparing primary responses. This mechanism generalized across distinct protease allergens, revealing mTORC1-driven metabolic reprogramming in sensory neurons as a form of innate neuroimmune memory underlying allergen cross-sensitization and polysensitization.