Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway.
Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway.
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DOI：
10.4049/jimmunol.182.1.581
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Komura H;Miksa M;Wu R;Goyert SM;Wang P
吞噬作用可防止垂死细胞释放潜在有害或免疫原性物质。乳脂肪球 EGF 因子 VIII (MFG-E8) 介导凋亡细胞的清除。我们之前已经证明，施用来自未成熟树突状细胞的富含 MFG-E8 的外泌体可以促进凋亡细胞的吞噬作用并提高脓毒症中的存活率。由于内毒素在多种微生物败血症中升高，我们假设 MFG-E8 的下调是通过 LPS-CD14 途径介导的，最终导致凋亡细胞的增加。在 CD14 缺陷型 (CD14−/−)、TLR4 突变型和野生型 (WT) 小鼠中通过盲肠结扎和穿刺 (CLP) 诱导多种微生物败血症。此外，腹腔注射LPS可引起内毒素血症。还通过用多粘菌素 B 预处理 CLP 诱导的 WT 小鼠来中和 LPS。在 CLP 后 5 小时和 20 小时或 LPS 给药后 5 小时评估脾 MFG-E8 表达、吞噬细胞活性和细胞凋亡。在脓毒症 WT 小鼠中，MFG-E8 mRNA 和蛋白质水平分别被抑制 49% 和 33%。内毒素血症以剂量依赖性方式降低 MFG-E8 mRNA 表达，并且多粘菌素 B 减弱了 CLP 诱导的败血症中 MFG-E8 mRNA 表达的下调。在 CD14−/− 和 TLR4 突变小鼠中均未观察到这种 CLP 诱导的抑制。 CLP 显着降低了 WT 小鼠腹膜巨噬细胞的吞噬活性（降低了 30%），但在 CD14−/− 小鼠中则没有。 CLP 还在 WT 小鼠的脾脏中诱导显着的细胞凋亡（61%），但在 CD14−/− 小鼠中较少。因此，脓毒症中 MFG-E8 的产生通过 LPS-CD14 依赖性方式下调，导致凋亡细胞的吞噬作用减少。
Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cells. Milk fat globule EGF-factor VIII (MFG-E8) mediates the clearance of apoptotic cells. We have previously shown that the administration of MFG-E8-rich exosomes from immature dendritic cells promotes the phagocytosis of apoptotic cells and improves survival in sepsis. Since endotoxin is elevated in polymicrobial sepsis, we hypothesized that downregulation of MFG-E8 is mediated via the LPS-CD14 pathway, eventually leading to the accruement of apoptotic cells. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in CD14-deficient (CD14−/−), TLR4-mutated and wild-type (WT) mice. In addition, endotoxemia was elicited by intraperitoneal injection of LPS. LPS was also neutralized by pre-treating CLP-induced WT mice with polymyxin B. Splenic MFG-E8 expression, phagocytic activity and apoptosis were assessed 5 h and 20 h after CLP or 5 h after LPS administration. In septic WT mice, MFG-E8 mRNA and protein levels were suppressed by 49% and 33%, respectively. Endotoxemia reduced MFG-E8 mRNA expression in a dose dependent manner and the downregulation of MFG-E8 mRNA expression in CLP-induced sepsis was attenuated by polymyxin B. This CLP-induced suppression was not observed in both CD14−/− and TLR4-mutated mice. CLP significantly decreased phagocytic activity of peritoneal macrophages in WT (by 30%), but not in CD14−/− mice. CLP also induced significant apoptosis in the spleen of WT (by 61%), but less in CD14−/− mice. Thus, MFG-E8 production is downregulated in sepsis by LPS-CD14 dependent fashion, leading to a reduction of phagocytosis of apoptotic cells.
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影响因子：
56.9
作者：
Blander, JM;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
15.9
作者：
Guo, RF;Huber-Lang, M;Ward, PA
通讯作者：
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DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
Karl, IE
影响因子：
3.1
作者：
Ebong, SJ;Goyert, SM;Remick, DG
通讯作者：
Remick, DG