Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages
Effective clearance of intracellular Leishmania major in vivo requires Pten in macrophages
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DOI：
10.1002/eji.200737302
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发表时间：
2008-05-01
影响因子：
5.4
通讯作者：
Suzuki, Akira
中科院分区：
文献类型：
--
作者：
Kuroda, Shoko;Nishio, Miki;Suzuki, Akira
利什曼病是一个主要的国际公共卫生问题，巨噬细胞是宿主抵抗这种寄生虫的关键。为了确定在染色体10上缺失的磷酸酶和张力蛋白同源物（Pten）（PI 3 K途径的负调节剂）是否在巨噬细胞介导的对利什曼原虫的抗性中起作用，我们产生了在巨噬细胞中特异性缺乏Pten的C57 BL/6小鼠（LysMCrePten（flox/flox）小鼠）。对由利什曼原虫感染引起的病变的检查表明，LysMCrePten（flox/flox）小鼠在感染的早期阶段比野生型（WT）小鼠对寄生虫更敏感，但最终能够消除病原体。体外Pten缺陷型巨噬细胞显示出响应IFN-γ处理的降低的杀死寄生虫的能力，这可能是因为突变细胞表现出与诱导型一氧化氮合酶表达和一氧化氮产生的降低相关的TNF分泌降低。在对各种TLR配体的反应中，Pten缺陷型巨噬细胞产生的TNF和IL-12比WT细胞少，但产生的IL-10比WT细胞多。然而，对引流淋巴结中的细胞进行分析L。主要接种部位表明LysMCrePtenflox/flox和WT小鼠在L.主要感染，与LysWrePten（flox/flox）小鼠最终消除寄生虫的能力一致。我们的研究结果表明，细胞内寄生虫的有效清除需要Pten在巨噬细胞。
Leishmaniases are a major international public health problem, and macrophages are crucial for host resistance to this parasite. To determine if phosphatase and tensin homologue deleted on chromosome ten (Pten), a negative regulator of the PI3K pathway, plays a role in macrophage-mediated resistance to Leishmania, we generated C57BL/6 mice lacking Pten specifically in macrophages (LysMCrePten(flox/flox) mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePten(flox/flox) mice were more susceptible to the parasite than wild-type (WT) mice in the early phase of the infection, but were eventually able to eliminate the pathogen. in vitro Pten-deficient macrophages showed a reduced ability to kill parasites in response to IFN-gamma treatment, possibly because the mutant cells exhibited decreased TNF secretion that correlated with reductions in inducible nitric oxide synthase expression and nitric oxide production. In response to various TLR ligands, Pten-deficient macrophages produced less TNF and IL-12 but more IL-10 than WT cells. However, analysis of cells in the lymph nodes draining L. major inoculation sites indicated that both LysMCrePtenflox/flox and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysWrePten(flox/flox) mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.