Efferocytosis induces macrophage proliferation to help resolve tissue injury.
Efferocytosis induces macrophage proliferation to help resolve tissue injury.
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DOI：
10.1016/j.cmet.2021.10.015
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发表时间：
2021-12-07
期刊：
影响因子：
29
通讯作者：
Tabas I
中科院分区：
文献类型：
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作者：
Gerlach BD;Ampomah PB;Yurdagul A Jr;Liu C;Lauring MC;Wang X;Kasikara C;Kong N;Shi J;Tao W;Tabas I
巨噬细胞对凋亡细胞的清除（efferocytosis）促进了凋亡信号通路，这可以由凋亡细胞吞噬溶酶体降解产生的分子触发。我们在这里表明，吞噬溶酶体dnes2a水解凋亡细胞DNA产生的核苷酸激活DNA - pkcs - mtorc2 /Rictor通路，增加Myc以促进非炎性巨噬细胞增殖。体外和小鼠实验中，efferocytic诱导的增殖扩大了溶解性巨噬细胞池，包括酶酶生诱导的腹膜炎、地塞米松诱导的胸腺细胞凋亡和动脉粥样硬化消退。在地塞米松-胸腺模型中，造血Rictor缺失阻断了efferocytosing巨噬细胞增殖、凋亡细胞清除和组织分解。在动脉粥样硬化消退过程中，沉默巨噬细胞Rictor或Dnase2a可阻断内皮细胞增殖、凋亡细胞清除和斑块稳定。鉴于先前的研究表明，其他类型的凋亡细胞货物可以促进个体efferocytosing巨噬细胞的溶解，本研究结果表明，信号触发的凋亡细胞衍生核苷酸可以通过增加这些巨噬细胞的数量来放大这种益处。巨噬细胞（efferocytosis）清除凋亡细胞（AC）促进组织分解，其失败导致炎症性疾病。Gerlach等人的研究表明，ac -核苷酸会引发efferocytosing巨噬细胞的增殖，这对于体内溶解（包括动脉粥样硬化消退）至关重要。这些发现可能为治疗炎症性疾病提供新的途径。
Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal Dnase2a activates a DNA–PKcs–mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or Dnase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages. Apoptotic cell (AC) clearance by macrophages (efferocytosis) promotes tissue resolution, and its failure contributes to inflammatory diseases. Gerlach at al. show that AC-nucleotides trigger efferocytosing macrophages to proliferate, which is essential for resolution in vivo, including in atherosclerosis regression. These findings may suggest new ways to treat non-resolving inflammatory diseases.
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影响因子：
29
作者：
Cai, Bishuang;Dongiovanni, Paola;Tabas, Ira
通讯作者：
Tabas, Ira
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
DOI：
10.1073/pnas.1524292113
发表时间：
2016-06-07
影响因子：
11.1
作者：
Cai, Bishuang;Thorp, Edward B.;Tabas, Ira
通讯作者：
Tabas, Ira
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
16.6
作者：
通讯作者：
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