Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA.
J Leukoc Biol. 2019 Jul;106(1):133-146. doi: 10.1002/JLB.3MIR1118-443R. Epub 2019 Jan 15.
Cold-inducible RNA-binding protein (CIRP) was discovered 2 decades ago while studying the mechanism of cold stress adaptation in mammals. Since then, the role of intracellular CIRP (iCIRP) as a stress-response protein has been extensively studied. Recently, extracellular CIRP (eCIRP) was discovered to also have an important role, acting as a damage-associated molecular pattern, raising critical implications for the pathobiology of inflammatory diseases. During hemorrhagic shock and sepsis, inflammation triggers the translocation of CIRP from the nucleus to the cytosol and its release to the extracellular space. eCIRP then induces inflammatory responses in macrophages, neutrophils, lymphocytes, and dendritic cells. eCIRP also induces endoplasmic reticulum stress and pyroptosis in endothelial cells by activating the NF-κB and inflammasome pathways, and necroptosis in macrophages via mitochondrial DNA damage. eCIRP works through the TLR4-MD2 receptors. Studies with CIRP mice reveal protection against inflammation, implicating eCIRP to be a novel drug target. Anti-CIRP Ab or CIRP-derived small peptide may have effective therapeutic potentials in sepsis, acute lung injury, and organ ischemia/reperfusion injuries. The current review focuses on the pathobiology of eCIRP by emphasizing on signal transduction machineries, leading to discovering novel therapeutic interventions targeting eCIRP in various inflammatory diseases.
冷诱导 RNA 结合蛋白 (CIRP) 是在研究哺乳动物对冷应激适应的机制时 20 年前发现的。从那时起，细胞内 CIRP (iCIRP) 作为应激反应蛋白的作用就得到了广泛的研究。最近，发现细胞外 CIRP (eCIRP) 也具有重要作用，作为一种损伤相关分子模式，对炎症性疾病的病理生物学提出了重要的影响。在出血性休克和败血症中，炎症会触发 CIRP 从核内转移到细胞质，并释放到细胞外空间。eCIRP 然后诱导巨噬细胞、中性粒细胞、淋巴细胞和树突状细胞的炎症反应。eCIRP 通过激活 NF-κB 和炎性小体途径在血管内皮细胞中诱导内质网应激和细胞焦亡，并通过线粒体 DNA 损伤在巨噬细胞中诱导坏死性凋亡。eCIRP 通过 TLR4-MD2 受体发挥作用。用 CIRP 小鼠进行的研究表明，它可以预防炎症，表明 eCIRP 是一个新的药物靶点。抗 CIRP Ab 或 CIRP 衍生的小肽在败血症、急性肺损伤和器官缺血/再灌注损伤中可能具有有效的治疗潜力。本综述重点介绍了 eCIRP 的病理生物学，强调了信号转导机制，从而发现了针对各种炎症性疾病的 eCIRP 的新型治疗干预措施。
