The Journal of investigative dermatology最新文献

To elucidate the complex effects of acute UVR on the skin, we exposed mouse skin to UVB and performed transcriptomic profiling of the epidermis, deep dermis, and adipose tissue. Spatial transcriptomic analysis revealed gene expression changes in the epidermis, dermis, and adipose. Whereas CD45⁺ immune cells showed differential expression of chemokines, cytokines, and acute-phase proteins, cytokeratin⁺ epidermal cells upregulated genes related to cellular stress and damage, structural remodeling, and apoptosis. Single-cell RNA sequencing 12 hours after UVR identified 4849 differentially expressed genes, with the epidermis and endothelial cells showing the highest differentially expressed gene counts. Pathway analysis of upregulated genes in the epidermis revealed enrichment in VEGF, HIPPO, complement, IL-6, and apoptosis signaling pathways. In endothelial cells, receptor-ligand analysis highlighted endothelial cells as key targets of CXCL chemokines and C3. In fibroblasts, UVR triggered the upregulation of inflammatory activation markers alongside genes associated with glucose metabolism. Cross-species comparison of UVR-responsive differentially expressed genes between mice and humans revealed strong concordance, particularly in TGF-β- and TNF-associated pathways. These results highlight the sequential activation of keratinocytes, fibroblasts, endothelial, and immune cells, providing mechanistic insights into how UVR can initiate or exacerbate autoimmune processes such as those observed in cutaneous lupus.

Signaling interactions between the dermal papilla and neighboring stem cells (SCs) in the hair germ and bulge regulate new follicle growth in the hair cycle. To study these interactions, the 3 populations had been profiled together by now-outdated microarrays or separately by bulk RNA sequencing. Recent single-cell transcriptomics established signatures of dermal papilla, bulge SCs, and hair germ SCs, but low detection sensitivity limited the depth of gene expression discovery. In this study, we define the transcriptomes of dermal papilla cells, bulge SCs, hair germ SCs, epidermal and follicle epithelial cells and dermal fibroblasts-after flow sorting each population from 4 neighboring mouse back skin regions-to gain deeper insights into the unique gene expression programs of hair follicle SCs and their instructive niche. With cross-comparisons of 56 whole-transcriptome measurements, we classify cell type-specific molecular signatures of enriched genes with unprecedented sensitivity. Joint analysis with signatures from 15 leading studies published in the last 20 years revealed many previously undescribed dermal papilla, bulge SC, and hair germ SC genes in mouse and human counterparts. With ligand-receptor mapping and CellChat analyses, we then uncover comprehensive cell-cell communication insights. Finally, we provide our transcriptome data in a full update of our Hair-GEL repository along with numerous signature and other gene tables for easy exploration of gene expression in hair follicle SCs and their niche.

Actinic keratosis (AK) is a precancerous, UV-induced skin lesion that can progress to cutaneous squamous cell carcinoma. Although UVR drives field cancerization and immunosuppression in the skin, keratinocyte-intrinsic responses to chronic, low-dose UV exposure have been insufficiently studied in AK. We established a patient-derived in vitro model using primary keratinocytes from AK lesions and age-matched, sun-exposed skin to investigate how repeated low-dose UV irradiation shapes keratinocyte stress responses. Integrating morphological profiling, cyclobutane pyrimidine dimer quantification, and bulk RNA sequencing, we observed morphological remodeling and accumulating DNA damage in AK keratinocytes despite activation of DNA repair and unfolded protein response pathways. Transcriptomic analyses revealed constitutive and UV-enhanced IFN signaling in AK cells, including upregulation of innate DNA sensing and ISGylation genes. Meta-analysis of 5 independent datasets validated IFN pathway activation as a conserved feature of AK, and IFNα exposure further sensitized AK keratinocytes to UV-induced cyclobutane pyrimidine dimer accumulation. Immunohistochemistry confirmed lesion-specific enrichment of ISG15 and UBE2L6 in AK epidermis, indicating spatially confined IFN pathway activation in vivo. Our model uncovers sustained IFN signaling and attenuated DNA damage repair as keratinocyte-intrinsic features of AK, suggesting that persistent IFN responses may modulate UV-induced damage responses and contribute to early photocarcinogenesis.

Although NLRP3 has been extensively studied in myeloid cells, its existence and regulation in epithelial cells, including keratinocytes, are unclear. In fact, whether human keratinocytes express a functional NLRP3 inflammasome at all remains a matter of debate in the inflammasome field. In this study, we provide additional evidence that NLRP3 is repressed in human keratinocytes cultured under noninflammatory conditions but can be sharply induced by IFNγ-but not lipopolysaccharide. In this IFNγ-primed state, not all established NLRP3 activators are specific to NLRP3. We report that nigericin-driven keratinocyte pyroptosis occurs through both NLRP1 and NLRP3, whereas Staphylococcus aureus α-hemolysin exclusively and nonredundantly activates NLRP3, even though both require K+ efflux. Furthermore, in the presence of T cells, certain virulent S aureus strains can cause NLRP3-dependent pyroptotic death in keratinocytes in vitro through the cooperative actions of superantigens and α-hemolysin. In summary, our findings establish the strict inducibility and functional relevance of the NLRP3 inflammasome in nonmyeloid, epithelial cells in vitro. These results resolve conflicting reports and position keratinocytes as a context-specific, nonhematopoietic cellular model for studying NLRP3 activation in host-microbe interactions at barrier tissues.