Primary alterations during the development of hidradenitis suppurativa.

BACKGROUND Hidradenitis suppurativa (HS) is a chronic, inflammatory disease of the apocrine gland-rich (AGR) skin region. The initial steps of disease development are not fully understood, despite intense investigations into immune alterations in lesional HS skin. OBJECTIVES We aimed to systematically investigate the inflammatory molecules involved in three stages of HS pathogenesis, including healthy AGR, non-lesional HS, and lesional HS skin, with the parallel application of multiple mRNA and protein-based methods. METHODS Immune cell counts (T cells, dendritic cells, macrophages), Th1/Th17-related molecules (IL-12B, TBX21, IFNG, TNFA, IL17, IL10, IL23A, TGFB1, RORC, CCL20), keratinocyte-related sensors (TLR2,4), mediators (S100A7, S100A8, S100A9, DEFB4B, LCN2, CAMP, CCL2), and pro-inflammatory molecules (IL1B, IL6, TNFA, IL23A) were investigated in the three groups by RNASeq, RT-qPCR, immunohistochemistry, and immunofluorescence. RESULTS Epidermal changes were already detectable in non-lesional HS skin; the epidermal occurrence of antimicrobial peptides (AMPs), IL-1β, TNF-α, and IL-23 were highly upregulated compared to healthy AGR skin. In lesional HS epidermis, TNF-α and IL-1β expression remained at high levels while AMPs and IL-23 increased even more compared to non-lesional skin. In the dermis of non-lesional HS skin, signs of inflammation were barely detectable (versus AGR), while in the lesional dermis, the number of inflammatory cells and Th1/Th17-related mediators were significantly elevated. CONCLUSIONS Our findings that non-lesional HS epidermal keratinocytes produce not only AMPs and IL-1β but also high levels of TNF-α and IL-23 confirm the driver role of keratinocytes in HS pathogenesis and highlight the possible role of keratinocytes in the transformation of non-inflammatory Th17 cells (of healthy AGR skin) into inflammatory cells (of HS) via the production of these mediators. The fact that epidermal TNF-α and IL-23 appear also in non-lesional HS seems to prove these cytokines as excellent therapeutic targets.