Carlos Alberto Mier-Aguilar

Background: Although ultraviolet B (UVB) radiation-induced immunosuppression is considered a key risk factor for skin cancer, individual susceptibility varies, and its mechanisms remain not fully understood. Objective: The current study collected skin biopsies from healthy volunteers before and after UVB radiation and linked UVB-induced effects in the skin to immunosuppression in the same individuals. Methods: A total of 62 healthy volunteers were recruited and randomly assigned to three groups: negative, positive, and UVB-exposed. Diphenylcyclopropenone was applied topically to induce contact hypersensitivity (CHS) responses. Skin punch biopsies were collected before and after UVB for analysis. Results: UVB exposure significantly suppressed CHS compared to the positive control. However, among 26 individuals, 7 (27%) were resistant (UVB-R), while the rest were susceptible (UVB-S) to UVB-induced immunosuppression. RNA-seq analysis of skin biopsies showed that UVB induced a higher level of immunosuppressive inflammation in UVB-S than in UVB-R individuals. Further analysis showed that UVB significantly activated the damage-associated molecular patterns only in UVB-S, but not in UVB-R individuals. Conclusion: Given the role of DAMP pathways in the development of inflammation, the results reveal a previously unrecognized mechanism: UVB-induced activation of DAMP pathways is linked to UVB-induced immunosuppressive inflammation in skin and susceptibility to immunosuppression in humans.

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell–cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked byS100A7/8/9andKRT6family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49f^highcells. The disruption of theS100Aenhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.