Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function.
Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function.
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DOI：
10.1084/jem.20091474
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发表时间：
2010-07-05
期刊：
影响因子：
--
通讯作者：
Trautwein C
中科院分区：
文献类型：
--
作者：
Sander LE;Sackett SD;Dierssen U;Beraza N;Linke RP;Müller M;Blander JM;Tacke F;Trautwein C
急性期蛋白（Acute-phase proteins, APPs）是一个进化上保守的蛋白家族，主要在肝脏对感染和炎症的反应中产生。尽管单个app具有广泛的促炎和抗炎特性，但它们在感染期间的集体功能仍不明确。通过小鼠多微生物脓毒症模型，我们发现通过肝细胞特异性gp130缺失（IL-6家族细胞因子共享的信号受体）来消除APP的产生，尽管正常的细菌清除，但仍会大大增加死亡率。通过STAT3传递肝脏gp130信号是控制全身性炎症所必需的。值得注意的是，肝脏gp130-STAT3的激活对于骨髓源性抑制细胞（MDSCs）的动员和组织积累也是必不可少的，MDSCs是一种主要以抗癌抗炎特性而闻名的细胞群。MDSCs对调节先天炎症至关重要，它们的过继性转移有效地保护gp130缺陷小鼠免于败血症相关的死亡。肝APPs血清淀粉样蛋白A和Cxcl1/KC共同促进MDSC的动员、积累和存活，逆转炎症失调，恢复gp130缺陷小鼠的存活。因此，肝脏和MDSCs之间的gp130依赖性通信通过app控制感染期间的炎症反应。
Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection.
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