Laboratório de Parasitologia Molecular, Instituto de Biofísica Carlos Chagas Filho, CCS, UFRJ, Rio de Janeiro, RJ, Brazil.
Departamento de Microbiologia e Parasitologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Brazil.
Eur J Immunol. 2018 Jul;48(7):1188-1198. doi: 10.1002/eji.201747257. Epub 2018 May 8.
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.
诱导型一氧化氮合酶 (iNOS) 的表达控制感染巨噬细胞内利什曼原虫的生长。组蛋白去乙酰化酶 (HDACs) 通过形成包含转录因子（如 NF-κB p50/50）的复合物来负调控基因表达。在此，我们证明了 p50/p50_HDAC1 占据与 H3K9Ac 水平降低相关的 iNOS 启动子。值得注意的是，我们发现感染 L. amazonensis 的巨噬细胞中 HDAC1 水平升高。在感染 L. major 的巨噬细胞中未发现 HDAC1 的上调。在敲低 HDAC1 的巨噬细胞中，寄生虫的细胞内负荷减少，同时一氧化氮水平升高。HDAC1 沉默导致 CBP/p300 占据 iNOS 启动子，以及 H3K9Ac 修饰的增加。重要的是，从感染 L. amazonensis 的髋关节反应性皮肤利什曼病患者的皮肤样本的免疫染色显示高水平的 HDAC1。简而言之，L. amazonensis 在感染的巨噬细胞中诱导 HDAC1，这有助于寄生虫的存活，并与感染 L. amazonensis 的患者中发现的髋关节反应性阶段有关。
