Distinct and shared effects of individual γ-secretase inhibitors on human keratinocytes

Gamma secretase (γ-secretase) is an enzymatic transmembrane complex responsible for the cleavage of over 100 substrates, including notch, E-cadherin, amyloid precursor protein, specific cytokine receptors, and other type I transmembrane proteins. Genetic variants in the γ-secretase complex are associated with familial hidradenitis suppurativa (HS), where they are predicted to inactivate enzymatic function. Further, γ-secretase inhibitors cause HS-like pathologies in patients with desmoid tumors. However, it is unclear how modulation of γ-secretase activity in keratinocytes impacts cellular processes and contributes to HS pathophysiology. We explored how the loss of γ-secretase function impacts keratinocyte-mediated inflammatory cytokine and chemokine production and adhesion, two key keratinocyte processes altered in HS. We used pharmacological inhibitors of γ-secretase (SCP0004, nirogacestat, and E2012) that have different mechanisms of action and substrate selectivity (eg, notch processing). Each inhibitor exhibited both distinct and similar effects on normal human keratinocyte functions. SCP0004 strongly modulated inflammatory cytokine responses. Nirogacestat modulated select chemokines and cytokines, whereas E2012 showed little effect. Conversely, keratinocyte adhesion was reduced by all γ-secretase inhibitors. Thus, γ-secretase inhibitors can drive keratinocyte functions associated with HS development. Future studies elucidating the contribution of specific substrates may inform the mechanisms of drug-induced HS phenotypes.