Hepatic acute phase proteins control innate immune responses during infection by promoting myeloid derived suppressor cell function

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 anti-inflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a murine model for polymicrobial sepsis we show here that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6-family cytokines, dramatically increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through signal transducer and activator of transcription (Stat)3 was required to control systemic inflammation. Notably, hepatic gp130/Stat3 activation was also a prerequisite to facilitate mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for anti-inflammatory properties in cancer. We show that MDSCs were critical to regulate innate inflammation and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. We identified serum amyloid A and Cxcl-1/KC as hepatic acute phase genes that cooperatively promoted MDSC mobilization, accumulation and survival. Administration of these proteins efficiently elevated MDSC numbers and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through acute phase proteins critically controls inflammatory responses during infection. Control [gp130f/f] and liver-specific Gp130 knockout [gp130delta(hepa)] mice were subjected to polymicrobial sepsis. Twelve hours after induction of sepsis mice were sacrificed and livers were removed. For control treatment mice were sacrified without any prior treatment. Total RNA was isolated and subjected to gene expression profiling.急性期蛋白（Acute phase proteins, APPs）是一类主要由肝脏在感染或炎症刺激下产生的进化保守蛋白家族。尽管单个APP已被证实具有广泛的促炎与抗炎特性，但它们在感染过程中的协同功能仍未被充分阐明。本研究采用多菌性脓毒症小鼠模型，通过肝细胞特异性敲除IL-6家族细胞因子共享的信号受体gp130以阻断急性期蛋白的产生，结果显示：尽管细菌清除能力未受影响，但小鼠的死亡率显著升高。肝脏内经由信号转导与转录激活因子3（signal transducer and activator of transcription, Stat3）介导的gp130信号通路，是调控全身炎症反应的必要条件。值得注意的是，肝脏gp130/Stat3通路的激活同时也是促进髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）动员与组织募集的必要前提——这类细胞在肿瘤领域中主要以抗炎特性被广泛认知。本研究证实，MDSCs对调控先天炎症反应至关重要，且过继转移MDSCs可有效保护gp130缺陷型小鼠免于脓毒症相关死亡。本研究鉴定出肝脏急性期基因血清淀粉样蛋白A（serum amyloid A）与趋化因子Cxcl-1/KC，二者可协同促进MDSCs的动员、募集与存活。外源性给予这两种蛋白，可有效提升MDSCs的数量，逆转异常活化的炎症反应，并恢复gp130缺陷型小鼠的存活率。综上，肝脏与MDSCs之间通过急性期蛋白介导的gp130依赖型信号互作，可关键调控感染过程中的炎症反应。实验分组：将对照小鼠[gp130f/f]与肝脏特异性gp130敲除小鼠[gp130Δ(hepa)]构建为多菌性脓毒症模型。于脓毒症诱导后12小时处死小鼠并摘取肝脏；对照组小鼠未经任何预处理直接处死。提取总RNA并进行基因表达谱分析。