7-dehydrocholesterol reductase inhibitors control Leishmania spp. in human macrophages

Leishmaniasis, caused by Leishmania spp., is a neglected parasitic disease with a broad clinical spectrum, whose treatments are toxic and present failures and resistance. Leishmania braziliensis and Leishmania amazonensis are highly prevalent species in Brazil. Cholesterol metabolism affects immune responses. 7-dehydrocholesterol reductase (DHCR7) converts 7-dehydrocholesterol (7-DHC) to cholesterol and this enzyme regulates macrophage polarization towards the M2 profile. Inhibiting DHCR7 enhances pro-inflammatory responses and may control infections, prompting investigation into its effects on Leishmania in macrophages. Human macrophages derived from THP-1 cells were infected with L. amazonensis or L. braziliensis for 24 h and treated with pharmacological DHCR7 inhibitors tamoxifen and AY9944. Inhibition of DHCR7 reduced infection by both Leishmania species in human macrophages. Additionally, DHCR7 inhibitors promoted an increase in the production of reactive oxygen intermediates (ROS) and in the production of TNF and IL-1β by human macrophages infected with L. amazonensis and L. braziliensis. These data suggest that DHCR7 inhibitors control Leishmania spp. infection in vitro and pave the way for new therapeutic approaches for this neglected disease.