CIRP increases ICAM-1(+) phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis.
CIRP increases ICAM-1(+) phenotype of neutrophils exhibiting elevated iNOS and NETs in sepsis.
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DOI：
10.1002/jlb.3a0817-327rr
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发表时间：
2018-04
影响因子：
5.5
通讯作者：
Wang P
中科院分区：
文献类型：
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作者：
Ode Y;Aziz M;Wang P
脓毒症代表由于感染引起的不受控制的炎症。冷诱导RNA结合蛋白（CIRP）是一种应激损伤相关分子模式（DAMP）。表达细胞间粘附分子-1（ICAM-1+中性粒细胞）的中性粒细胞亚群先前被证明产生高水平的活性氧。CIRP在脓毒症期间对ICAM-1+中性粒细胞的发育和功能的作用尚不清楚。我们假设CIRP诱导中性粒细胞ICAM-1表达，导致脓毒症期间肺损伤。使用盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型，我们发现CIRP表达增加，肺中ICAM-1+中性粒细胞的频率和数量增加。相反，CIRP−/−小鼠在败血症中与WT小鼠相比，肺中ICAM-1+中性粒细胞的频率和数量显示出显著抑制。在体外用重组鼠CIRP（rmCIRP）处理骨髓源性中性粒细胞（BMDN）以时间和剂量依赖性方式显著增加ICAM-1+表型。与用同种型IgG或DMSO处理的BMDN相比，在用抗TLR 4 Ab或NF-κB抑制剂处理的BMDN中，rmCIRP对ICAM-1+中性粒细胞频率增加的作用显著减弱。rmCIRP处理的ICAM-1+ BMDN中诱导型一氧化氮合酶（iNOS）产生和中性粒细胞胞外陷阱（NET）形成表型的频率显著高于ICAM-1− BMDN。脓毒症后，肺中ICAM-1+中性粒细胞的iNOS和NET水平显著高于ICAM-1−中性粒细胞。我们进一步揭示了ICAM-1和NET共定位于用rmCIRP处理的中性粒细胞中。CIRP−/−小鼠在脓毒症中的存活率（78%存活率）比WT小鼠（48%存活率）有显著改善。因此，CIRP可能是一种新的治疗靶点，用于调节脓毒症期间肺中iNOS产生和NETs形成ICAM-1+中性粒细胞。我们的研究结果涉及CIRP，ICAM-1+中性粒细胞和NET暗示了脓毒症诱导的急性肺损伤的新病理生理学，靶向CIRP可能是控制脓毒症诱导的急性肺损伤的有效治疗工具。
Sepsis represents uncontrolled inflammation due to an infection. Cold-inducible RNA-binding protein (CIRP) is a stress-induced damage-associated molecular pattern (DAMP). A subset of neutrophils expressing intercellular adhesion molecule-1 (ICAM-1+ neutrophils) was previously shown to produce high levels of reactive oxygen species. The role of CIRP for the development and function of ICAM-1+ neutrophils during sepsis is unknown. We hypothesize that CIRP induces ICAM-1 expression in neutrophils causing injury to the lungs during sepsis. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found increased expression of CIRP and higher frequencies and numbers of ICAM-1+ neutrophils in the lungs. Conversely, the CIRP−/− mice showed significant inhibition in the frequencies and numbers of ICAM-1+ neutrophils in the lungs as compared to WT mice in sepsis. In vitro treatment of bone marrow-derived neutrophils (BMDN) with recombinant murine CIRP (rmCIRP) significantly increased ICAM-1+ phenotype in a time- and dose-dependent manner. The effect of rmCIRP on increasing frequencies of ICAM-1+ neutrophils was significantly attenuated in BMDN treated with anti-TLR4 Ab or NF-κB inhibitor as compared, respectively, with BMDN treated with isotype IgG or DMSO. The frequencies of inducible nitric oxide synthase (iNOS) producing and neutrophil extracellular traps (NETs) forming phenotypes in rmCIRP-treated ICAM-1+ BMDN were significantly higher than those in ICAM-1− BMDN. Following sepsis the ICAM-1+ neutrophils in the lungs showed significantly higher levels of iNOS and NETs compared to ICAM-1− neutrophils. We further revealed that ICAM-1 and NETs were co-localized in the neutrophils treated with rmCIRP. CIRP−/− mice showed significant improvement in their survival outcome (78% survival) over that of WT mice (48% survival) in sepsis. Thus, CIRP could be a novel therapeutic target for regulating iNOS producing and NETs forming ICAM-1+ neutrophils in the lungs during sepsis. Our findings involving CIRP, ICAM-1+ neutrophils and NETs implicate a novel pathophysiology of sepsis-induced acute lung injury, and targeting CIRP could be an effective therapeutic tool to control sepsis-induced acute lung injury.