Neutrophils in Sepsis: Role of CIRP

这个R01项目的目标是研究冷诱导的机制 RNA结合蛋白(CIRP)增加了脓毒症的严重程度，并导致急性肺损伤(ALI)。脓毒症和阿里是 致命的，没有FDA批准的治疗方法。CIRP是一种核蛋白，可以释放到细胞内 脓毒症时的循环，增加了脓毒症的严重程度，并导致ALI。我们发现CIRP 增加了一种新的中性粒细胞亚群，其特征是细胞间黏附分子的表面表达- 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张，但不是 在CIRP基因敲除小鼠中。我们进一步表明，用CIRP刺激足以诱导ICAM-1+ 中性粒细胞。我们第一次发现，CIRP诱导的ICAM-1+中性粒细胞产生更高的 中性粒细胞胞外陷阱(Net)水平。基于这些新的发现，我们假设CIRP 诱导网状细胞间黏附分子-1+中性粒细胞在脓毒症中引起ALI。我们还发现了C23，一种源自 从人CIRP中，剂量依赖地抑制CIRP诱导的肿瘤坏死因子-α的释放，并抑制CIRP诱导的 ICAM-1+中性粒细胞。因此，我们进一步假设C23通过减少CIRP-1而减轻脓毒症所致的ALI。 诱导的网状中性粒细胞。我们将首先演示CIRP对网络形成ICAM-1+的诱导 中性粒细胞及其在体外和体内的有害作用。接下来，我们将确定关键的信号通路 CIRP通过此途径诱导网状ICAM-1+中性粒细胞。最后，我们将检验C23的S能力 抑制ICAM-1+中性粒细胞的净形成，降低脓毒症和ALI的严重程度，提高脓毒症的存活率。 这些研究将提高我们对CIRP如何诱导网状中性粒细胞引起 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.