Sensory nerve-associated, IL-31-secreting M2 macrophages (SNAMs) promote substance P-induced neurogenic inflammation in human skin ex vivo

Summary: Abstract Body: Sensory-neuron-associated macrophages (SNAMs) are a subset of dermal M2 macrophages that communicate with cutaneous sensory nerve fibers (NFs) through the secretion of cytokines like IL-31, thereby contributing to inflammatory pruritic disorders like atopic dermatitis (AD) and prurigo nodularis (PN). Since the influence of neuropeptides on SNAMs in human skin remains incompletely understood, we have explored this in denervated, organ-cultured, full-thickness, healthy human eyelid skin (3-5 donors) by administering substance P (SP, 10-8M), the key neuropeptide that mediates stress responses and neurogenic skin inflammation, to the culture medium. SP significantly upregulated the expression of the pro-inflammatory pruritogen, periostin, and increased the total number and % of M2 macrophages (CD68+CD206+), particularly IL-31+ M2 macrophages. To explore this mechanistically, eyelid biopsies were organ-cultured with either a periostin-neutralizing antibody or the neurokinin-1 receptor (NK-1R) antagonist, aprepitant, in the presence/absence of SP. This showed that aprepitant diminished the SP-induced periostin upregulation, while aprepitant and periostin-neutralization abrogated the SP-induced increase in the number of dermal IL-31+ M2 macrophages. These ex vivo data suggest that SP release from cutaneous sensory NFs propagates neurogenic inflammation in human skin through NK-1R activation, increasing periostin secretion and promoting IL-31+ M2 SNAMs. This vicious circle aggravates neurogenic skin inflammation, pointing to NK-1R activation (on SNAMs?) and periostin as novel therapeutic targets to break this pathogenic loop; for example, by administering aprepitant to patients with AD or PN. Sofia M. Perez¹, Jennifer Gherardini², Leigh A. Nattkemper¹, Tatiana Gomez-Gomez¹, Gil Yosipovitch¹, Wendy Lee³, Jeremy Cheret^{1, 2}, Ralf Paus^{1, 2} 1. Dermatology, University of Miami Miller School of Medicine, Miami, FL, United States. 2. CUTANEON-Skin&Hair Innovations GmbH, Hamburg&Berlin, Germany. 3. University of Miami Health System Bascom Palmer Eye Institute, Miami, FL, United States. Innate Immunity, Microbiology, and Microbiome