Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism. Issue 7 (8th May 2018)

• Record Type: Journal Article
• Authors: Calegari‐Silva, Teresa C.; Vivarini, Áislan C.; Pereira, Renata de M. S.; Dias‐Teixeira, Karina L.; Rath, Carolina T.; Pacheco, Amanda S. S.; Silva, Gabrielle B. L.; Pinto, Charlene A. S.; dos Santos, José V.; Saliba, Alessandra M.; Corbett, Carlos E. P.; de Castro Gomes, Claudia M.; Fasel, Nicolas; Lopes, Ulisses G.
• Is Part Of: European journal of immunology. Volume 48:Issue 7(2018)
• Page Start: 1188
• Page End: 1198
• Publication Date: 2018-05-08
• Subjects: HDAC1 -- Leishmaniasis -- Macrophage -- Parasitse; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747257
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: 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. Abstract : Leishmania amazonensis infection induces NF‐κB p50/p50 and increases the nuclear levels of HDAC1 in macrophages. In the nucleus, p50/50 binds to nk promoter sequences and recruits HDAC1, forming a repression complex leading to H3K9 deacetylation and consequent iNOS promoter silencing. The absence of Nitric Oxide production favors the amastigote growth.