Inhibition of Gamma-secretase activity without interfering in Notch signaling decreases inflammatory response in patients with cutaneous leishmaniasis: Gamma-secretase inhibition in cutaneous leishmaniasis

ABSTRACTCutaneous leishmaniasis (CL) patients present an exacerbated inflammatory response associated with tissue damage and ulcer development. Increasing numbers of patients have exhibited treatment failure, which remains not well understood. We hypothesized that adjuvant anti-inflammatory therapy would benefit CL patients. The aim of the present study was to investigate the contribution of Notch signaling and gamma-secretase activity to the inflammatory response observed in CL patients. Notch signaling is a molecular signaling pathway conserved among animal species. Gamma-secretase forms a complex of proteins that, among other pathways, modulates Notch signaling and immune response. We found that Notch 1 cell receptor signaling protects against the pathologic inflammatory response, and JLK6, a gamma-secretase inhibitor that does not interfere with Notch signaling, was shown to decrease the in-vitro inflammatory response in CL. Our data suggest that JLK6 may serve as an adjuvant treatment for CL patients.