FOXP3+macrophage represses acute ischemic stroke-induced neural inflammation
FOXP3+macrophage represses acute ischemic stroke-induced neural inflammation
复制标题
FOXP3巨噬细胞抑制急性缺血性中风诱发的神经炎症
DOI：
10.1080/15548627.2022.2116833
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发表时间：
2022-09-29
期刊：
影响因子：
13.3
通讯作者：
Lu，Zhengqi
中科院分区：
文献类型：
--
作者：
Cai，Wei;Hu，Mengyan;Lu，Zhengqi
适当终止细胞死亡诱导的神经炎症是急性缺血性卒中（AIS）组织修复的前提。巨噬细胞清除细胞尸体/碎片并产生协调免疫反应的炎症介质。在此，我们报道了Tregs的关键免疫抑制转录因子FOXP3在脑卒中病变的巨噬细胞中有条件表达。巨噬细胞中FOXP3消融导致有害的卒中结果，强调了FOXP3+巨噬细胞的有益作用。FOXP3+巨噬细胞不同于M1或M2亚群，并表现出超活跃的efferocytic能力。通过scRNAseq和CUT & RUN分离FOXP3结合的dna分析，我们发现FOXP3通过促进货物代谢促进巨噬细胞吞噬。FOXP3的表达受静息巨噬细胞巨噬/自噬蛋白降解的控制，而lc3相关吞噬（LAP）的启动竞争性地占据了自噬机制，从而允许FOXP3激活。我们的数据表明一组独特的FOXP3+巨噬细胞具有增强的清除能力，可能是针对AIS的免疫调节治疗的靶点。ADGRE1/F4/80：粘附G蛋白偶联受体E1；AIF1/Iba1：同种异体移植物炎症因子1；AIS：急性缺血性卒中；ARG1：精氨酸酶1；ATP：三磷酸腺苷；BECN1/Beclin1: Beclin1，与自噬相关；BMDM：骨髓源性巨噬细胞；CKO：条件击倒；CSF1/M-CSF：集落刺激因子1（巨噬细胞）；CSF2/GM-CSF：集落刺激因子2；CSF3/G-CSF：集落刺激因子3；CUT & RUN：在靶标下切割并利用核酸酶释放；CyD：细胞松弛素D；DAMP：危险/损伤相关的分子模式；DIL：二十八烷基-3,3,3,3-四甲基十二碳菁；ELISA：酶联免疫吸附法；GO：基因本体；FCGR3/CD16: Fc受体，IgG，低亲和力III；HMGB1：高迁移率组框1；IFNG/IFNγ：干扰素γ；知识产权:免疫沉淀反应;京都基因与基因组百科全书；ITGAM/CD11b：整合素亚基α M；ITGAX/CD11c：整合素亚基α X；LAP: lc3相关吞噬；LC-MS：液相色谱-质谱法；有限合伙人:脂多糖;MRC1/CD206：甘露糖受体，C型1；O4：少突胶质细胞标记物O4；PBMC：外周血单核细胞；RBC：红细胞；PTPRC/CD45：蛋白酪氨酸磷酸酶，受体类型，C；RBFOX3/NeuN: RNA结合蛋白，fox1同源物（秀丽隐杆线虫）3；RUBCN/Rubicon：含有RUN结构域和富含半胱氨酸结构域的Beclin - 1相互作用蛋白；scRNAseq：单细胞RNA测序；SQSTM1/p62 (sequestosome 1)；TGFB/TGFβ：转化生长因子；tMCAO：短暂性大脑中动脉闭塞；TNF/TNFα：肿瘤坏死因子；Treg：调节性T细胞。
ABSTRACT Proper termination of cell-death-induced neural inflammation is the premise of tissue repair in acute ischemic stroke (AIS). Macrophages scavenge cell corpses/debris and produce inflammatory mediators that orchestrate immune responses. Here, we report that FOXP3, the key immune-repressive transcription factor of Tregs, is conditionally expressed in macrophages in stroke lesion. FOXP3 ablation in macrophages results in detrimental stroke outcomes, emphasizing the beneficial role of FOXP3+ macrophages. FOXP3+ macrophages are distinct from the M1 or M2 subsets and display superactive efferocytic capacity. With scRNAseq and analysis of FOXP3-bound-DNA isolated with CUT & RUN, we show that FOXP3 facilitates macrophage phagocytosis through enhancing cargo metabolism. FOXP3 expression is controlled by macroautophagic/autophagic protein degradation in resting macrophages, while initiation of LC3-associated phagocytosis (LAP) competitively occupies the autophagic machineries, and thus permits FOXP3 activation. Our data demonstrate a distinct set of FOXP3+ macrophages with enhanced scavenging capability, which could be a target in immunomodulatory therapy against AIS. Abbreviations: ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AIF1/Iba1: allograft inflammatory factor 1; AIS: acute ischemic stroke; ARG1: arginase 1; ATP: adenosine triphosphate; BECN1/Beclin1: Beclin 1, autophagy related; BMDM: bone marrow-derived macrophages; CKO: conditional knockout; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; CUT & RUN: cleavage under targets and release using nuclease; CyD: cytochalasin D; DAMP: danger/damage-associated molecular pattern; DIL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine; ELISA: enzyme linked immunosorbent assay; GO: Gene Ontology; FCGR3/CD16: Fc receptor, IgG, low affinity III; HMGB1: high mobility group box 1; IFNG/IFNγ: interferon gamma; IP: immunoprecipitation; KEGG: Kyoto Encyclopedia of Genes and Genomes; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; LC-MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MRC1/CD206: mannose receptor, C type 1; O4: oligodendrocyte marker O4; PBMC: peripheral blood mononuclear cells; RBC: red blood cells; PTPRC/CD45: protein tyrosine phosphatase, receptor type, C; RBFOX3/NeuN: RNA binding protein, fox 1 homolog (C. elegans) 3; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; scRNAseq: single cell RNA sequencing; SQSTM1/p62 (sequestosome 1); TGFB/TGFβ: transforming growth factor, beta; tMCAO: transient middle cerebral artery occlusion; TNF/TNFα: tumor necrosis factor; Treg: regulatory T cell.