Divergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain.
Divergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain.
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DOI：
10.1161/strokeaha.120.032196
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发表时间：
2021-05
期刊：
影响因子：
8.3
通讯作者：
Sansing LH
中科院分区：
文献类型：
--
作者：
Chang CF;Goods BA;Askenase MH;Beatty HE;Osherov A;DeLong JH;Hammond MD;Massey J;Landreneau M;Love JC;Sansing LH
脑组织内的小胶质细胞和单核细胞源性巨噬细胞（MDMs）是先天免疫细胞，参与炎症反应、碎片吞噬和损伤后的组织修复。我们之前报道过小胶质细胞和MDMs在脑出血（ICH）后几天内从促炎表型转变为修复表型。然而，它们在大脑中的个体功能特性在很大程度上仍然未知。在这里，我们描述了小胶质细胞和MDMs之间的差异，并进一步阐明了它们不同的激活状态和对脑出血后病理生理和恢复的功能贡献。采用自体血液注射法建立小鼠脑出血模型。在ICH和naïve对照后的第1、3、7和10天，对小鼠分离的小胶质细胞和MDMs进行纵向转录组学分析，发现了区分这些细胞的核心转录程序。采用流式细胞术和体内吞噬实验研究小胶质细胞和MDMs的吞噬能力。抗原呈递通过卵清蛋白- otii CD4 t细胞增殖试验与骨髓源性巨噬细胞和原代小胶质细胞培养来评估。在脑出血大鼠脑内，MDMs具有较高的吞噬活性和红细胞吞噬能力。脑出血后MDMs和小胶质细胞的差异基因表达显示出不同的转录特征。MDMs在各时间点的主要组织相容性复合体II类基因表达均高于小胶质细胞，诱导抗原特异性t细胞增殖的能力更强。小胶质细胞和MDMs的不同个体发生导致炎症脑中的不同反应和功能，因为这两种细胞群在脑出血后的大脑中具有不同的吞噬功能和抗原呈递能力。
Brain tissue-resident microglia and monocyte-derived macrophages (MDMs) are innate immune cells that contribute to the inflammatory response, phagocytosis of debris, and tissue repair after injury. We have previously reported that both microglia and MDMs transition from proinflammatory to reparative phenotypes over days after an intracerebral hemorrhage (ICH). However, their individual functional properties in the brain remain largely unknown. Here we characterized the differences between microglia and MDMs and further elucidate their distinct activation states and functional contributions to the pathophysiology and recovery after ICH. Autologous blood injection was used to model ICH in mice. Longitudinal transcriptomic analyses on isolated microglia and MDMs from mice at days 1, 3, 7 and 10 after ICH and naïve controls identified core transcriptional programs that distinguish these cells. Imaging flow cytometry and in vivo phagocytosis assays were used to study phagocytic ability of microglia and MDMs. Antigen presentation was evaluated by ovalbumin-OTII CD4 T-cell proliferation assays with bone marrow-derived macrophages and primary microglia cultures. MDMs had higher phagocytic activity and higher erythrophagocytosis in the ICH brain. Differential gene expression revealed distinct transcriptional signatures in the MDMs and microglia after ICH. MDMs had higher expression of major histocompatibility complex class II genes than microglia at all time points and greater ability to induce antigen-specific T-cell proliferation. The different ontogeny of microglia and MDMs lead to divergent responses and functions in the inflamed brain as these two cell populations differ in phagocytic functions and antigen-presenting capabilities in the brain after ICH.