Estudo de vias de regulação da resposta inflamatória em pacientes com Leishmaniose Cutânea causada por L. braziliensis

Abstract

Patients with cutaneous leishmaniasis (CL) present an exacerbated inflammatory response associated with tissue damage and the development of ulcers. In recent years, higher rates of treatment failure with pentavalent antimoniate have been observed, but the underlying reason remains poorly understood. Our hypothesis is that patients with CL present a decrease in regulatory mechanisms, thus allowing inflammation to persist and ulcers to develop. The objectives of the present study were to evaluate the role of Notch signaling, activation of PPAR-y by pioglitazone and the functions of PGE2 in the inflammatory response of patients with CL caused by L. braziliensis. We initially discovered that signaling via the Notch 1 receptor protects patients with CL against the pathological inflammatory response, while the compound JLK6, a selective gamma-secretase inhibitor that does not interfere with Notch signaling, has been shown to decrease the inflammatory response in vitro, without change the parasite load in monocytes after 72 hours. Subsequently, we showed that activation of PPAR-γ by pioglitazone changed the profile of monocytes to M2, decreasing the inflammatory response without affecting the killing of L. braziliensis by monocytes from patients with CL. Finally, we found that increased COX-2/PGE2 is associated with disease severity and treatment failure in CL. Furthermore, neutralization of COX-2 by NS398, a selective NSAID, increased the ability of macrophages to kill L. braziliensis, thus decreasing the production of inflammatory cytokines. Together, these findings reveal the advantages of inhibiting the gamma-secretase complex with the compound JLK6 without interfering with Notch signaling, activating PPAR-y with pioglitazone and inhibiting the synthesis of PGE2 through neutralization of COX-2 with the compound NS398. Making these three compounds strong candidates for adjuvant therapy for CL.