Inhibition of Efferocytosis by Extracellular CIRP-Induced Neutrophil Extracellular Traps.
Inhibition of Efferocytosis by Extracellular CIRP-Induced Neutrophil Extracellular Traps.
复制标题
DOI：
10.4049/jimmunol.2000091
复制
发表时间：
2021-02-15
期刊：
影响因子：
--
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Chen K;Murao A;Arif A;Takizawa S;Jin H;Jiang J;Aziz M;Wang P
巨噬细胞（efferocytosis）对凋亡细胞的吞噬清除在败血症中受损，但其机制尚不清楚。细胞外冷诱导rna结合蛋白（eCIRP）是一种促进炎症的新型损伤相关分子模式（DAMP）。我们发现，ecirp诱导的中性粒细胞胞外陷阱（NETs）通过一种新机制损害efferocytosis。巨噬细胞和凋亡胸腺细胞在重组小鼠（rm） cirp诱导的NETs存在下共同培养，可显著抑制efferocytosis。在rmcirp处理的野生型（WT）存在下，Efferocytosis被显著抑制，但没有PAD4−/−中性粒细胞。注射rmcirp的PAD4 - / -小鼠腹腔内的Efferocytosis高于WT小鼠。乳脂球- egf -因子VIII （MFG-E8）增加了巨噬细胞的efferocysis，而添加MFG-E8后，NETs对efferocysis的抑制作用没有恢复，表明NETs破坏了MFG-E8的受体αvβ3或αvβ5整合素。我们发现NETs中的中性粒细胞弹性酶（NE）通过切割巨噬细胞表面整合素αvβ3和αvβ5显著抑制efferocytosis。使用临床前脓毒症模型，我们发现CIRP - / -小鼠与WT小鼠相比，腹腔内的efferocytosis率显着增加。我们发现了ecirp诱导的NETs通过ne依赖性地降低巨噬细胞αvβ3/αvβ5整合素来抑制efferocytosis的新作用。靶向eCIRP通过增强胞浆功能改善脓毒症。
Phagocytic clearance of apoptotic cells by the macrophages (efferocytosis) is impaired in sepsis, but its mechanism is poorly understood. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel damage-associated molecular pattern (DAMP) which fuels inflammation. We identify that eCIRP-induced neutrophil extracellular traps (NETs) impair efferocytosis through a novel mechanism. Co-culture of macrophages and apoptotic thymocytes in the presence of recombinant murine (rm) CIRP-induced NETs significantly inhibited efferocytosis. Efferocytosis was significantly inhibited in the presence of rmCIRP-treated wild-type (WT), but not PAD4−/− neutrophils. Efferocytosis in the peritoneal cavity of rmCIRP-injected PAD4−/− mice was higher than WT mice. Milk fat globule-EGF-factor VIII (MFG-E8) increased macrophage efferocytosis, while the inhibition of efferocytosis by NETs was not rescued upon addition of MFG-E8, indicating disruption of MFG-E8’s receptor(s) αvβ3 or αvβ5 integrin by the NETs. We identified neutrophil elastase (NE) in the NETs significantly inhibited efferocytosis by cleaving macrophage surface integrins αvβ3 and αvβ5. Using a pre-clinical model of sepsis, we found that CIRP−/− mice exhibited significantly increased rate of efferocytosis in the peritoneal cavity compared to WT mice. We discovered a novel role of eCIRP-induced NETs to inhibit efferocytosis by the NE-dependent decrease of αvβ3/αvβ5 integrins in macrophages. Targeting eCIRP ameliorates sepsis by enhancing efferocytosis.
登录
查看更多内容
富含甘氨酸的RNA结合蛋白，介导了对哺乳动物细胞生长的冷诱导抑制。
影响因子：
7.8
作者：
Nishiyama, H;Itoh, K;Kaneko, Y;Kishishita, M;Yoshida, O;Fujita, J
通讯作者：
Fujita, J
影响因子：
18.4
作者：
Eruslanov EB;Singhal S;Albelda SM
通讯作者：
Albelda SM
影响因子：
5.7
作者：
Friggeri, Arnaud;Banerjee, Sami;Liu, Gang
通讯作者：
Liu, Gang
影响因子：
3.7
作者：
Petretto, Andrea;Bruschi, Maurizio;Migliorini, Paola
通讯作者：
Migliorini, Paola
影响因子：
7.3
作者：
Rohrbach AS;Slade DJ;Thompson PR;Mowen KA
通讯作者：
Mowen KA