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Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism

2018; Wiley; Volume: 48; Issue: 7 Linguagem: Inglês

10.1002/eji.201747257

1521-4141

Teresa Calegari-Silva, Áislan de Carvalho Vivarini, Renata M. Pereira, Karina Luiza Dias Teixeira, Carolina Torturella Rath, Amanda S. S. Pacheco, Gabrielle B. L. Silva, Charlene A. S. Pinto, José Vitorino dos Santos, Alessandra Mattos Saliba, Carlos Eduardo Pereira Corbett, Cláudia Maria de Castro Gomes, Nicolás Fasel, Ulisses Gazos Lopes,

Signaling Pathways in Disease

The induced expression of nitric oxide synthase (iNOS) controls the intracellular growth of Leishmania in infected macrophages. Histones deacetylases (HDACs) negatively regulate gene expression through the formation of complexes containing transcription factors such as NF-κB p50/50. Herein, we demonstrated the occupancy of p50/p50_HDAC1 to iNOS promoter associated with reduced levels of H3K9Ac. Remarkably, we found increased levels of HDAC1 in L. amazonensis-infected macrophages. HDAC1 upregulation was not found in L. major-infected macrophages. The parasite intracellular load was reduced in HDAC1 knocked-down macrophages, which presented increased nitric oxide levels. HDAC1 silencing led to the occupancy of CBP/p300 to iNOS promoter and the rise of H3K9Ac modification. Importantly, the immunostaining of skin samples from hiporeactive cutaneous leishmaniasis patients infected with L. amazonensis, revealed high levels of HDAC1. In brief, L. amazonensis induces HDAC1 in infected macrophages, which contribute to parasite survival and is associated to hiporeactive stage found in L. amazonensis infected patients.