803 Epidermal inflammatory activity is an important driver of hidradenitis suppurativa lesions

Abstract

Hidradenitis suppurativa (HS) is an inflammatory skin disorder of the pilosebaceous unit defined by painful nodules, tunnels, and scarring. Previous studies documented dermal cell infiltrate and the abundance of inflammatory cytokines in HS lesions, including TNFα, IL-17, and IL-1β. However, not much is currently known about the contribution of keratinocytes and immune cell activity within the epidermis in HS. We found that the degree of epidermal inflammation in HS lesions positively correlated with Hurley stage of disease (r =0.746; p=0), indicating the evolution of epidermal responses with disease severity. Keratinocytes were the primary producers of TNFα (p<0.05) and IL-6 (p<0.05) in HS lesions at all Hurley stages. Increased expression of CXCL3 (5-fold; p<0.01) in keratinocytes of stage III lesions positively correlated with increased recruitment of neutrophils to stage III lesional epidermis. Compared to healthy keratinocytes, enhanced production of chemokines from HS keratinocytes, including CCL22 (stage II 4-fold; p=0.09) and CCL3 (stages II and III p<0.05; 30-fold and 10-fold respectively), was associated with CD8 T cell infiltration and corresponding chemokine receptor expression in the epidermis. These recruited immune cells strongly produce or enable the production of IFNγ (>50 fold), IL-17A (500-fold), and IL-1β (5 to 10-fold), as well as IFNβ1, CXCL10, and STAT1 (HS II/III lesions; p<0.05 for all) by multiple cell types locally in the epidermis, likely generating positive feedback for increased inflammation. As epidermal inflammation evolves during disease progression and contributes to immune cell recruitment, our data suggest that topical therapeutics that block cytokine and chemokine production from the epidermis may be efficacious in HS. In all, our results collectively indicate that keratinocytes are not simply bystanders in HS inflammatory events, but rather actively contribute to HS pathogenesis.