mTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis.
mTORC2 signalling regulates M2 macrophage differentiation in response to helminth infection and adaptive thermogenesis.
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DOI：
10.1038/ncomms14208
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发表时间：
2017-01-27
影响因子：
16.6
通讯作者：
Horton MR
中科院分区：
文献类型：
--
作者：
Hallowell RW;Collins SL;Craig JM;Zhang Y;Oh M;Illei PB;Chan-Li Y;Vigeland CL;Mitzner W;Scott AL;Powell JD;Horton MR
替代活化的巨噬细胞（M2）在对寄生蠕虫的先天免疫应答中具有重要功能，并且新出现的证据也表明这些细胞是全身代谢的调节剂。在这里，我们显示了mTORC 2信号在M2巨噬细胞生成中的关键作用。通过选择性条件性缺失衔接子分子Rictor消除巨噬细胞中的mTORC 2信号传导抑制了M2巨噬细胞的生成，同时保持经典活化巨噬细胞（M1）的生成完整。巨噬细胞中Rictor的选择性缺失阻止了小鼠中寄生蠕虫感染的M2分化和清除，并且还消除了小鼠调节棕色脂肪和维持核心体温的能力。我们的研究结果定义了mTORC 2在巨噬细胞中整合来自免疫微环境的信号以促进先天性2型免疫以及整合全身代谢和产热反应中的作用。mTORC 1和mTORC 2是T细胞分化为Th 1/Th 17或Th 2细胞所必需的。在这里，作者表明mTORC 2信号传导也是IL-4诱导的M2激活所必需的，由N. brasiliensis感染模型和冷攻击来模拟适应性产热。
Alternatively activated macrophages (M2) have an important function in innate immune responses to parasitic helminths, and emerging evidence also indicates these cells are regulators of systemic metabolism. Here we show a critical role for mTORC2 signalling in the generation of M2 macrophages. Abrogation of mTORC2 signalling in macrophages by selective conditional deletion of the adaptor molecule Rictor inhibits the generation of M2 macrophages while leaving the generation of classically activated macrophages (M1) intact. Selective deletion of Rictor in macrophages prevents M2 differentiation and clearance of a parasitic helminth infection in mice, and also abrogates the ability of mice to regulate brown fat and maintain core body temperature. Our findings define a role for mTORC2 in macrophages in integrating signals from the immune microenvironment to promote innate type 2 immunity, and also to integrate systemic metabolic and thermogenic responses. mTORC1 and mTORC2 are alternatively required for differentiation of T cells into Th1/Th17 or Th2 cells. Here the authors show mTORC2 signalling is also needed for IL-4-induced M2 activation with functional evidence provided by a N. brasiliensis infection model and cold challenge to model adaptive thermogenesis.