Sympathetic Neuron Hyperactivation Drives Hair Follicle Necrosis and T Cell Autoreactivity

Stress profoundly affects health, but the mechanisms driving stress-induced tissue changes remain poorly understood. Here, we show that strong acute stress drives rapid hair loss and initiates autoimmunity. Under stress, hyperactivated sympathetic nerves release excessive norepinephrine, causing necrosis in rapidly dividing hair follicle transit-amplifying cells (HF-TACs) while sparing most hair follicle stem cells (HFSCs). This differential sensitivity to stress stems from differences in cell death genes, metabolic strategies, and calcium homeostasis. Together, these factors render HF-TACs more vulnerable to the sudden calcium surges triggered by norepinephrine. HF-TAC necrosis releases cellular debris that triggers macrophage clearance and dendritic cell activation, ultimately leading to the activation and amplification of autoreactive T cells that can attack the hair follicle. Our findings reveal mechanistically how stress causes immediate tissue damage in the highly proliferative HF-TACs via sympathetic nerve-induced necrosis, which in turn fuels the activation of a T cell-mediated response against the hair follicle. Overall design: Cell type: FACS purified cells from mouse skin; 3 conditions: 12H, and 72H RTX treated vs control; 2 replicate for each condition.