Perceived stress exacerbates psoriasis in human skin in vivo: Insights from a humanized psoriasis mouse model

Abstract

IntroductionThe widely held belief that psychoemotional stress triggers or exacerbates psoriatic skin lesions lacks sufficient scientific evidence. This study investigated this concept using a psoriasis humanized mouse model. MethodsHealthy human skin was grafted onto SCID/beige mice (n=25), and one month later, psoriatic lesions were induced by intradermal injection of autologous, in vitro IL-2- preactivated PBMCs. Following lesion development, topical dexamethasone (DEX) was applied to induce lesion remission. After lesions disappeared, the mice were exposed to either sonic or sham stress for 24 hours. ResultsSonic stress led to the relapse of psoriatic lesions in all human skin xenografts within 14 days. This relapse was associated with significant changes in psoriasis-related skin characteristics: increased epidermal thickness, K16 expression, keratinocyte proliferation, antimicrobial peptide expression (S100A7, h{beta}2-defensin), and immune activation markers (HLA-DR, ICAM-1, CD1d, MICA-NKG2D). Additionally, epidermal and dermal immune cells (CD3+, CD8+, CD11c+, CD56+, ILC3, c-KIT+ or tryptase+ cells) and psoriasis-associated pro-inflammatory mediators (CXCL10, IL-22, IL-15, IL-17A/F, IFN-{gamma}, and TNF) were found to be increased. Neurogenic inflammation biomarkers (NGF, NK1-R, and substance P) were also significantly upregulated in stressed mice. Treatment with the FDA-approved neurokinin-1 receptor antagonist, aprepitant, prevented stress-induced psoriatic relapses in 4 out of 5 mice and normalized most inflammatory and neurobiological markers. ConclusionsThese findings provide novel, conclusive evidence that perceived stress can trigger psoriatic lesions in human skin xenografts in vivo and highlight the role of substance P-dependent neurogenic inflammation in this process.