A neuroimmune axis linking S100A8/9 to itch sensitization in both bullous pemphigoid and atopic dermatitis

Bullous pemphigoid and atopic dermatitis are both inflammatory skin disorders characterized by intense pruritus and type 2 immune responses. Previous studies identified S100A8 and S100A9 as highly upregulated genes in perilesional skin of both conditions. Here, we demonstrate that S100A8/9 is highly expressed in the keratinocytes and infiltrating immune cells in bullous pemphigoid and atopic dermatitis skin and elevated in the serum of patients with bullous pemphigoid. Notably, infiltrating neutrophils in the perilesional skin, one of the major sources of secreted S100A8/9, are in close proximity to the cutaneous nerves, suggesting neuroimmune interactions. Using calcium imaging analysis, we show that S100A8/9 directly excite nociceptive sensory neurons in a toll-like receptor 4-dependent manner. Toll-like receptor 4 is expressed in a unique subset of nociceptive neurons that co-express histamine receptor H1. Intriguingly, mouse behavioral analyses reveal that S100A8/9 potentiates histamine-evoked scratching. Together, these results suggest S100A8/9 as a shared neuroimmune amplifier of histaminergic itch in T helper 2-driven dermatoses.