Epithelial sodium channel inhibition as a targeted therapy for skin inflammation

Inflammatory skin disease is characterized by a pathologic inflammatory interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is often used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify novel targets, potentially impacting epidermal pathways, we carried out a non-biased informatics screen to identify drug entities with an inverse transcriptional signature to keratinocyte inflammatory signals. Using psoriasis, a prototypic inflammatory skin disease as model, we utilized pharmacologic, transcriptomic and proteomic characterization to find that benzamil, the benzyl derivative of the FDA-approved diuretic amiloride, effectively reversed keratinocyte-driven inflammatory signaling. Orthogonal validation across transgenic, chemically induced and xenograft models of skin inflammation indicate that benzamil perturbs pathogenic interactions between the small GTPase Rac1 and its adaptor NCK1, reduce STAT3 and NFκβ signaling and downstream cytokine production in keratinocytes. Inhibition of sodium channels prevents excess Rac1-NCK1 binding, rescues pro-inflammatory signaling pathways in patient keratinocytes without systemic immunosuppression, and can effectively be accomplished through both systemic and topical intervention. We show that small molecule inhibition of epithelial sodium channels is a potent novel therapeutic avenue for treating skin inflammation.