Solar urticaria involves rapid mast cell STAT3 activation and neutrophil recruitment, with FcεR1 as an upstream regulator

Background Solar urticaria is a rare photodermatosis characterised by rapid onset sunlight-induced urticaria, but its pathophysiology is not well understood. Objective To define the cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar simulated ultraviolet radiation (SSR), and compare with healthy controls (HC). Methods Cutaneous biopsies were taken from unexposed skin and skin exposed to a single low (physiological) dose of SSR, at 30 minutes, 3 and 24 hours post-exposure, in n=6 solar urticaria patients and n=6 HC. Biopsies were assessed by immunohistochemistry and bulk RNA-sequencing analysis. Results In solar urticaria, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple pro-inflammatory cytokine and chemokine genes were upregulated (including IL20, IL6, CXCL8) or identified as upstream regulators (including TNF, IL1β, IFNγ). IgE and FcεR1 were identified as upstream regulators, and phosphorylated STAT3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours post-SSR exposure, suggesting a mechanism of mast cell activation. Clinical resolution of solar urticaria by 24 hours mirrored resolution of inflammatory gene signature profiles. Comparison with available datasets of chronic spontaneous urticaria showed transcriptomic similarities relating to immune activation but several transcripts were identified solely in solar urticaria including CXCL8 and CSF2/3. Conclusions Solar urticaria is characterised by rapid STAT3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with FcεR1 engagement indicated as an early event.