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

BACKGROUND: Solar urticaria is a rare photodermatosis characterized by rapid-onset sunlight-induced urticaria, but its pathophysiology is not well understood. OBJECTIVE: We sought to define cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar-simulated UV radiation (SSR) and compare with healthy controls (HC). METHODS: Cutaneous biopsy specimens were taken from unexposed skin and skin exposed to a single low (physiologic) dose of SSR at 30 minutes, 3 hours, and 24 hours after exposure in 6 patients with solar urticaria and 6 HC. Biopsy specimens were assessed by immunohistochemistry and bulk RNA-sequencing analysis. RESULTS: In solar urticaria specimens, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple proinflammatory cytokine and chemokine genes were upregulated (including IL20, IL6, and CXCL8) or identified as upstream regulators (including TNF, IL-1ß, and IFN-γ). IgE and FcεRI were identified as upstream regulators, and phosphorylated signal transducer and activator of transcription 3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours after 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 characterized by rapid signal transducer and activator of transcription 3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with FcεRI engagement indicated as an early event.

EGFR/MEK inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege.

AIMS: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated protein kinase (MEKi) induce a folliculitis in 75-90% of patients, whose pathobiology remains insufficiently understood. OBJECTIVES: (1) Characterize changes in the skin immune status and global transcriptional profile of EGFRi-treated patients (2) Probe whether EGFRi affects the hair follicle's (HF) immune privilege (IP) (3) Identify early pro-inflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from long-term EGFRi-treated patients exhibiting folliculitis (Chronic-EGFRi, n=9) vs normal scalp skin (n=9) and patients prior to commencing EGFRi therapy and after two weeks of EGFRi therapy (Acute-EGFRi, n=5). Healthy organ-cultured scalp HFs were exposed to EGFRi (Erlotinib) or MEKi (Cobimetinib) (n=5 patients, each). Samples were assessed by quantatitive immunohistomorphometry, RNAseq and in situ hybridization. RESULTS: The Chronic-EGFRi cohort showed CD8+ T cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated MHC class I, ß2-microglobulin and MHC class II and decreased TGF-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of HLA-A, HLA-DR, ß2-microglobulin transcripts. RNAseq anlysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and IL-26 in Chronic-EGFRi biopsies, as well as increased interlukin IL-33 and decreased IL-37 expesssion in both Acute-EGFRi biopsies and organ-cultured HFs. CONCLUSION: These data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

Activation of the integrated stress response in human hair follicles.

Unravelling how energy metabolism and stress responses are regulated in human scalp hair follicles could reveal novel insights into the controls of hair growth and provide new targets to manage hair loss disorders. The Mitochondrial Pyruvate Carrier (MPC) imports pyruvate, produced via glycolysis, into the mitochondria, fuelling the TCA cycle. Previous work has shown that MPC inhibition promotes lactate generation, which activates murine epithelial hair follicle stem cells (eHFSCs). However, by pharmacologically targeting the MPC in short-term human hair follicle ex vivo organ culture experiments using UK-5099, we induced metabolic stress-responsive proliferative arrest throughout the human hair follicle epithelium, including within Keratin 15+ eHFSCs. Through transcriptomics, MPC inhibition was shown to promote a gene expression signature indicative of disrupted FGF, IGF, TGFß and WNT signalling, mitochondrial dysfunction, and activation of the integrated stress response (ISR), which can arrest cell cycle progression. The ISR, mediated by the transcription factor ATF4, is activated by stressors including amino acid deprivation and ER stress, consistent with MPC inhibition within our model. Using RNAScope, we confirmed the upregulation of both ATF4 and the highly upregulated ATF4-target gene ADM2 on human hair follicle tissue sections in situ. Moreover, treatment with the ISR inhibitor ISRIB attenuated both the upregulation of ADM2 and the proliferative block imposed via MPC inhibition. Together, this work reveals how the human hair follicle, as a complex and metabolically active human tissue system, can dynamically adapt to metabolic stress.