Project description:Background Hidradenitis suppurativa (HS), psoriasis (PsO) and atopic dermatitis (AD) are inflammatory skin diseases which, despite sharing some immunological pathways, have unique disease pathogenesis and distinct pathology. For example, Th17 cells are central to PsO pathogenesis and have also been implicated in HS inflammation. AD, on the other hand, is classically referred to as a Th2-mediated disease, however incidence of AD is twice as likely in HS patients compared with healthy individuals, demonstrating an association between HS and AD. Objective To date the transcriptomics of HS, PsO and AD have not been directly compared. Therefore this study aimed to evaluate the transcriptomic differences between HS, PsO and AD lesions to identify a biological signature that defines HS inflammation. Methods Bulk RNA sequencing was performed on 19 healthy controls, 15 HS, 21 PsO and 15 AD lesional skin samples. Results Principal component analysis (PCA) identified a distinct transcriptome in HS lesions compared with healthy control skin, with increased expression of inflammatory mediators and more active inflammatory pathways including TNF, IL-17 and B cell signalling pathways. PsO lesions were defined by a strong IL-17 signature and while an IL-17 signature existed in HS lesions, HS was distinguished from PsO lesions by a unique B cell signature. When compared to AD lesions, HS lesions had a more complex inflammatory profile involving TNF, B cell and NLR signalling while AD lesions had high expression of Th2-associated genes. Weighted gene co-expression analysis suggested T cell signalling and epidermal development are important characteristics of PsO lesions while HS lesions can be defined by complement activation, B cell signalling and fibroblast-associated pathways indicating the potential for scarring in HS. Cell type deconvolution identified an enrichment of keratinocytes and T cells in PsO, Th2 cells in AD and B cells and plasma cells in HS. Finally, gene expression analysis identified increased expression of B cell, plasma cell and immunoglobulin-associated genes in HS lesions relative to healthy control skin, PsO and AD lesions. Conclusion These data suggest that HS pathogenesis is more complex than AD or PsO and highlights an important role of B and plasma cells in HS inflammation.

Project description:Calcium and 1,25-dihydroxyvitamin D3 (1,25D3), through the actions of their respective receptors, the Ca2+-sensing receptor (CaSR) and the vitamin D receptor (VDR), potentiate keratinocyte differentiation. VDR regulates epidermal keratinocyte proliferation and differentiation by modulating gene transcription, whereas the CaSR, a member of the family C G-protein coupled receptor, calcium mobilizes intracellular calcium and induces the formation of cell-cell junctions. 1,25D3 augments the sensitivity of the prodifferentiating actions of calcium by increasing the expression of CaSR. CaSR- and VDR-deficient keratinocytes share common characteristics such as abnormal intercellular adhesion and sphigolipid metabolism. Both CaSR and VDR are abundantly expressed in epidermal stem cell populations including CD34 expressing bulge keratinocytes in hair follicles and basal cells in interfollicular epidermis. To delineate the role of CaSR- and VDR-dependent pathways in regulating epidermal development and functions in physiological state, we generated conditional CaSR-null and VDR-null mice, where Casr and VDR gene was removed from keratinocytes. Keratinocyte-specific CaSR-null and VDR-null mice manifest distinct phenotypes. CaSR-null mice display defective epidermal permeability barrier function due to aberrant keratinocyte differentiation. VDR-null mice develop alopecia after completing the first hair follicle cycling. Concurrent ablation of CaSR and VDR genes in keratinocytes delays rate of wound repair and increases incidence of skin tumor formation to a greater extent than deletion of the CaSR or VDR alone, indicative of synergistic effects of calcium and 1,25D3 signaling. Gene expression profiles and subsequent pathway analysis on the epidermis derived from 5-day-old neonates revealed that ablation of CaSR or VDR increased expression of genes associated with cancer progression and metastasis. Deletion of VDR markedly inhibited signaling pathways that regulate hair development. Furthermore, concurrent ablation of CaSR and VDR significantly suppressed calcium, VDR, Wnt/b-catenin signaling, as well as epithelial adherence junction signaling to maintain appropriate keratinocyte adhesion. These results indicated the interplay of calcium/CaSR and 1,25D3/VDR signaling in keratinocyte proliferation and differentiation, and their importance in maintaining normal epidermal adhesion and functions. n=3 CON and KO (each sample contain RNA isolated from neonatal epidermis separated from 3 mice)

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Pathogenic Keratinocyte States and Fibroblast Niches Define the Tissue Microenvironment in Severe Hidradenitis Suppurativa

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