Neutrophils in Sepsis: Role of CIRP

项目描述：这个R 01项目的目标是研究冷诱导的 RNA结合蛋白（CIRP）增加脓毒症的严重程度，并导致急性肺损伤（ALI）。脓毒症和急性肺损伤 没有FDA批准的治疗方法CIRP是一种核蛋白，可以被释放到细胞中。 脓毒症期间的血液循环，增加脓毒症的严重程度并引起ALI。我们发现CIRP 增加了一个新的中性粒细胞亚群，其特征是细胞间粘附分子的表面表达， 1（ICAM-1）。我们发现，ICAM-1+中性粒细胞在脓毒症小鼠的血液和肺中扩增，但在脓毒症小鼠的血液和肺中没有扩增。 在CIRP敲除小鼠中。我们进一步表明，用CIRP刺激足以诱导ICAM-1+表达。 中性粒细胞我们第一次发现CIRP诱导的ICAM-1+中性粒细胞产生了更高的ICAM-1， 中性粒细胞胞外陷阱（NETs）。基于这些新的发现，我们假设CIRP 诱导NET形成ICAM-1+中性粒细胞引起脓毒症中的ALI。我们还表明，C23，一种肽衍生物， 从人CIRP中，剂量依赖性地抑制CIRP诱导的TNF-α释放， ICAM-1+中性粒细胞。因此，我们进一步假设C23通过降低CIRP-1来减弱脓毒症诱导的ALI。 诱导NET形成中性粒细胞。我们将首先证明CIRP诱导NET形成ICAM-1+ 中性粒细胞及其有害作用，在体外和体内。接下来，我们将确定关键的信号通路 CIRP通过其诱导NET形成ICAM-1+中性粒细胞。最后，我们将研究C23的能力， 抑制NET形成ICAM-1+中性粒细胞，降低脓毒症和ALI严重程度，并增加脓毒症存活率。 这些研究将提高我们对CIRP如何诱导NET形成中性粒细胞引起 炎症和组织损伤，并支持C23作为一种新的有效治疗方法的发展， 脓毒症和ALI患者。

PROJECT DESCRIPTION: This R01 project's goal is to investigate the mechanism by which cold-inducible RNA-binding protein (CIRP) increases sepsis severity and causes acute lung injury (ALI). Sepsis and ALI are deadly and have no FDA-approved treatment. CIRP is a nuclear protein that can be released into the circulation during sepsis, increasing sepsis severity and causing ALI. We have discovered that CIRP increases a novel subset of neutrophils characterized by surface expression of intercellular adhesion molecule- 1 (ICAM-1). We found that ICAM-1+ neutrophils were expanded in the blood and lungs of septic mice, but not in CIRP knockout mice. We further showed that stimulation with CIRP was sufficient to induce ICAM-1+ neutrophils. For the first time, we discovered that CIRP-induced ICAM-1+ neutrophils produced much higher levels of neutrophil extracellular traps (NETs). Based on these novel findings, we hypothesize that CIRP induces NET-forming ICAM-1+ neutrophils to cause ALI in sepsis. We also showed that C23, a peptide derived from human CIRP, dose-dependently inhibits CIRP-induced release of TNF-α and inhibits CIRP induction of ICAM-1+ neutrophils. Thus, we further hypothesize that C23 attenuates sepsis-induced ALI by reducing CIRP- induced NET-forming neutrophils. We will first demonstrate CIRP's induction of NET-forming ICAM-1+ neutrophils and their deleterious effects, both in vitro and in vivo. Next, we will identify key signaling pathways through which CIRP induces NET-forming ICAM-1+ neutrophils. Finally, we will examine C23's ability to suppress NET-forming ICAM-1+ neutrophils, decrease sepsis and ALI severity, and increase sepsis survival. These studies will improve our understanding of how CIRP induces NET-forming neutrophils to cause inflammation and tissue injury and support the development of C23 as a new and effective treatment for patients with sepsis and ALI.