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 activate 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.

巨噬细胞对凋亡细胞的清除（胞吐作用）促进了信号通路的分解，这可以由凋亡细胞的吞噬溶酶体降解衍生的分子触发。我们在此展示了源自吞噬溶酶体 DNase2a 水解凋亡细胞 DNA 的核苷酸激活 DNA-PKcs-mTORC2/Rictor 通路，该通路增加 Myc 以促进非炎性巨噬细胞增殖。Efferocytosis 诱导的增殖扩大了体外分解巨噬细胞的池在小鼠中，包括酵母聚糖诱导的腹膜炎、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辨率。在动脉粥样硬化消退中，沉默巨噬细胞 Rictor 或 DNase2a 阻断了 efferocyte 增殖、凋亡细胞清除和斑块稳定。鉴于以前的工作表明其他类型的凋亡细胞货物可以促进单个 efferocytosing 巨噬细胞的分辨率，这里的研究结果表明，信号触发的凋亡细胞衍生的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。