Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway
Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway
复制标题
小鼠 FHR-1 同源物 FHR-E 的缺乏通过增强 LPS 诱导的替代补体途径加速败血症和急性肾损伤
DOI：
10.3389/fimmu.2020.01123
复制
发表时间：
2020-06-19
影响因子：
7.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Li, Xiangru;Hao, Zhenhua;Li, Wei
补体旁路途径（AP）在严重威胁生命的脓毒症的发生发展中起重要作用。作为AP的调节因子的H因子相关蛋白1（FHR-1）的缺乏被认为是非典型溶血性尿毒症综合征（阿胡斯）和其他类型肾病的易感因素，当存在诱导物如感染时。然而，疾病发展的潜在机制在很大程度上是未知的。CFHR 1基因敲除在动物感染模型中的应用尚未见报道，其在体内的功能尚不清楚。在此，产生aCfhr 1敲除小鼠用于研究脓毒症和脓毒症诱导的急性肾损伤（阿基）中的AP。我们发现，小鼠FHR-1同源物（FHR-E）缺陷增强了脂多糖（LPS）诱导的AP激活，在体外和体内，Cfhr 1基因敲除小鼠表现出更严重的脓毒症和阿基响应LPS挑战。这些结果表明，FHR-E缺乏通过AP过度激活促进LPS诱导的脓毒症和阿基，为研究AP调节和脓毒症提供了小鼠模型。本研究揭示了FHR-E在体内的功能，为进一步研究FHR-1缺陷相关疾病的发病机制提供了线索。
Alternative complement pathway (AP) plays an important role in the development of sepsis, which is life threatening. Deficiency of factor H-related protein 1 (FHR-1), which is a regulator of AP, has been considered as a susceptible factor for atypical hemolytic uremic syndrome (aHUS) and other types of nephropathy when an inducer such as infection exists. However, the underlying mechanism of the disease development is largely unknown. There is no report onCFHR1gene knockout in any animal infection model and its functionin vivois still unclear. Here, aCfhr1knockout mouse was generated for investigating AP in sepsis and sepsis-induced acute kidney injury (AKI). We found that murine FHR-1 homolog (FHR-E) deficiency enhanced lipopolysaccharide (LPS)-induced AP activation bothin vitroandin vivoand thatCfhr1knockout mice exhibited more severe sepsis and AKI in response to LPS challenge. These results indicated that FHR-E deficiency promoted LPS-induced sepsis and AKI through AP over-activation, providing a mouse model for studying AP regulation and sepsis. This study revealed the function of FHR-Ein vivo, which may further provide hints to the pathogenesis of FHR-1 deficiency-related diseases by enhancing LPS-induced AP activation.