A critical role for MMP3 during amplification of skin inflammation by psychological stress

Summary: Abstract Body: Psychological stress decreases antimicrobial defense and increases susceptibility to S. aureus infection in mice by activating the HPA axis and inhibiting host defense functions of immune-acting fibroblasts. However, in contrast to decreased innate antimicrobial defense, imiquimod (IMQ)-induced skin inflammation is amplified by stress in this model. To understand this dichotomy, RNASeq was performed on mice following restraint-induced stress and topical IMQ. This revealed that stress increased expression in the skin of a spectrum of chemokines associated with immune cell recruitment, notably neutrophil markers (Ly6g, Retnlg, Cd177; fold change > 135) and significantly enriched IL-17 and TNF-α signaling pathways. Notably, upregulation of fibroblast-associated genes (Mmp3, Mmp9) was observed in mice after stress. Analysis of human data sets revealed a similar induction of MMP3 in human psoriasis, with elevated MMP3 mRNA expression in lesional psoriasis (p = .031, n = 67) and increased MMP3 protein levels in serum (p = .025, n = 23). To determine if MMP3 expression is directly influenced by inflammation and stress, we treated dermal fibroblasts with a cytokine cocktail to mimic inflammation (IL-17A+TNF-α) and the stress hormone adrenaline. Mmp3 mRNA was induced 17.8-fold by adrenaline, increased 34.5-fold in the presence of IL-17A+TNF-α, and further increased 1.67-fold by the addition of IL-17A+TNF-α+adrenaline. To explore the significance of this response, mice undergoing stress and IMQ treatment were treated with a specific MMP-3 inhibitor (UK356618). This reduced inflammation in stressed mice treated with IMQ to control levels by normalizing epidermal thickness and decreasing neutrophil recruitment (p < .0001). In summary, our results reveal the previously unrecognized activation of MMP-3 by stress, and that the action of MMP-3 promotes skin inflammation. These findings further increase understanding of fibroblast function in inflammatory skin diseases and offers potential new therapeutic targets. Hung M. Chan¹, Fengwu Li¹, Richard L. Gallo¹ 1. Dermatology, University of California San Diego, La Jolla, CA, United States. Innate Immunity, Microbiology, and Microbiome