Complement C1q and sepsis associated fatalities

项目摘要 脓毒症是一种危及生命的全身性炎症性疾病，具有对感染的失调的宿主反应。 虽然已经发现了驱动疾病病理学的基于炎症的关键器官功能障碍， 这种综合征通常很难识别，目前发表的预后标准也很难识别这些综合征 注定会因这种情况而死去。我们在改善脓毒症疾病预后方面的努力持续失败， 主要是由于患者反应的实质异质性。即使年龄，性别和医疗条件相似 合并症，尽管有很好的支持努力，但患者死亡率存在很大的异质性。 本研究中，（1）我们发现在重症患者中出现的CD49c+中性粒细胞亚群独立地 预测败血症的死亡率。(2)我们进一步发现，与脓毒症相关的中性粒细胞亚群 死亡率显著上调补体成分C1q的基因表达。(3)重要的是， 脓毒症幸存者的中性粒细胞表达更高水平的C1q蛋白，而死亡患者的中性粒细胞不能表达C1q蛋白。 维持中性粒细胞中C1q的表达。(4)在小鼠脓毒症模型中，用中和 抗体或有条件地敲除中性粒细胞中的C1q导致败血症死亡率显著增加。（五） 用C1q治疗脓毒症小鼠显著提高了存活率。根据这些初步观察， 我们的首要假设是中性粒细胞C1q是脓毒性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来控制它们自身的清除， 在败血症中损伤器官。因此，C1q是减轻炎症损伤的药物靶点 感染脓毒症患者，从而提高了生存率。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目标2将调查 C1q调节脓毒症消退的机制，包括C1q依赖的吞噬作用， 嗜中性粒细胞凋亡和巨噬细胞分化。目标3将研究潜在的机制， C1q表达不均一。目的4将确定重组C1q及其突变变体对 败血症小鼠的存活率。总的来说，这项建议涉及有关机制如何失调， 宿主的反应威胁着病人的生存，并提供了一个分子靶点，用于抑制病毒的破坏性武器。 同时促进疾病消退和组织恢复。

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.