Complement C1q and sepsis associated fatalities

项目总结 脓毒症是一种威胁生命的全身炎症状态，宿主对感染的反应失调。 尽管驱动疾病病理的关键的基于炎症的器官功能障碍已经被发现， 这种综合征通常很难辨认，目前公布的预后标准很难识别这些 注定要死于这种病症。我们在改善脓毒症疾病预后方面的努力继续失败 主要是由于患者反应的实质上的异质性。即使年龄、性别和医疗条件相似， 合并症：尽管做出了很好的支持努力，但患者死亡率仍有很大的异质性。 在这里，(1)我们发现CD49c中性粒细胞亚群独立地出现在危重患者身上。 可以预测败血症的死亡率。(2)进一步发现中性粒细胞亚群与脓毒症相关。 病死率显著上调补体成分C1q的基因表达。(3)重要的是， 败血症幸存者的中性粒细胞表达更高水平的C1q蛋白，而已故患者未能表达 维持中性粒细胞C1q的表达。(4)在小鼠脓毒症模型中，用中和方法阻断C1q 抗体或有条件地敲除中性粒细胞中的C1q会导致败血症死亡率的显著增加。(5) C1q可显著提高脓毒症小鼠的存活率。根据这些初步观察， 我们的主要假设是，中性粒细胞C1q是脓毒症死亡率的可靠预后生物标志物。它 进一步假设凋亡的中性粒细胞释放C1q来控制其自身的清除 脓毒症时损伤的器官。因此，C1q是减轻炎症损伤的可用药靶点。 对败血症患者的治疗，从而提高存活率。在目标1中，我们将确定 ICU患者外周血中性粒细胞C1q表达与脓毒症死亡率的关系目标2将调查 C1q调节脓毒症分解的机制，包括C1q依赖的吞噬作用 中性粒细胞凋亡与巨噬细胞分化。目标3将调查潜在的机制 异源C1q表达。目的4将确定重组C1q及其突变体对 败血症小鼠的存活。综上所述，这项提案解决了有关监管不善的人如何 宿主的反应威胁到患者的生存，并提供了一个分子靶点来抑制宿主的破坏性手臂 在促进疾病消退和组织恢复的同时，进行高炎症反应。

PROJECT SUMMARY Sepsis is a life-threatening systemic inflammatory condition with dysregulated host responses to an infection. Although key hyperinflammation-based organ dysfunctions that drive disease pathology have been discovered, the syndrome is often difficult to recognize, and current published prognostic criteria poorly identify those destined to die with the condition. Continued failure of our efforts in improving disease prognosis in sepsis is mainly due to substantial heterogeneity in the patient response. Even with similar age, sex, and medical comorbidities, there is a substantial heterogeneity in the patient mortality despite excellent supportive efforts. Here, (1) we discovered that a subpopulation of CD49c+ neutrophil arising in critically ill patients independently predicts mortality from sepsis. (2) We further found that the neutrophil subpopulation associated with septic fatality dramatically upregulated gene expression of the complement component C1q. (3) Importantly, neutrophils from septic survivors expressed higher levels of C1q protein, while deceased patients failed to maintain C1q expression in their neutrophils. (4) In mouse sepsis models, blocking C1q with neutralizing antibodies or conditionally knocking out C1q in neutrophils led to a significant increase in septic mortality. (5) Treatment of septic mice with C1q drastically increased the survival. Based on these preliminary observations, our overarching hypothesis is that neutrophil C1q is a reliable prognostic biomarker of septic mortality. It is hypothesized further that apoptotic neutrophils release C1q to control their own clearance in critically injured organs during sepsis. Thus, C1q is a druggable target for attenuation of inflammatory damage to septic patients with resulting improvement in survival. In Aim 1, we will determine the correlation between C1q expression in peripheral blood neutrophils and sepsis mortality in ICU patients. Aim 2 will investigate the mechanisms by which C1q regulates the resolution of sepsis, including C1q-dependent phagocytosis of apoptotic neutrophils and differentiation of macrophages. Aim 3 will investigate mechanisms underlying the heterogenous C1q expression. Aim 4 will determine the effects of recombinant C1q and its mutant variants on the survival of septic mice. Taken together, this proposal addresses mechanisms regarding how the dysregulated host response threatens patient survival and offers a molecular target for dampening the destructive arms of the hyperinflammatory response while promoting disease resolution and tissue recovery.