Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, USA.
Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.
FASEB J. 2020 Jul;34(7):9771-9786. doi: 10.1096/fj.202000482R. Epub 2020 Jun 7.
Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern (DAMP). Intercellular adhesion molecule-1 (ICAM-1) expressing neutrophils produce excessive amounts of neutrophil extracellular traps (NETs). We reveal that eCIRP generates ICAM-1 neutrophils through triggering receptor expressed on myeloid cells-1 (TREM-1) and the ICAM-1 neutrophils involve Rho GTPase to promote NETosis. Treatment of BMDN with rmCIRP increased the frequency of ICAM-1 BMDN, while rmCIRP-treated TREM-1 BMDN or pretreatment of BMDN with TREM-1 inhibitor LP17 significantly decreased the frequency of ICAM-1 neutrophils. The frequencies of ICAM-1 neutrophils in blood and lungs were markedly decreased in rmCIRP-injected mice or septic mice treated with LP17. Coculture of ICAM-1 neutrophils or wild-type (WT) neutrophils with WT macrophages in the presence of a peptidylarginine deiminase 4 (PAD4) inhibitor reduced TNF-α and IL-6 compared to WT neutrophils treated with rmCIRP. Treatment of ICAM-1 neutrophils with rmCIRP resulted in reduced quantities of NETs compared to WT rmCIRP-treated neutrophils. Treatment of BMDN with rmCIRP-induced Rho activation, while blockade of ICAM-1 significantly decreased Rho activation. Inhibition of Rho significantly decreased rmCIRP-induced NET formation in BMDN. TREM-1 plays a critical role in the eCIRP-mediated increase of ICAM-1 expression in neutrophils, leading to the increased NET formation via Rho activation to exaggerate inflammation.
细胞外冷诱导 RNA 结合蛋白（eCIRP）是一种损伤相关分子模式（DAMP）。表达细胞间黏附分子-1（ICAM-1）的中性粒细胞产生大量中性粒细胞胞外诱捕网（NETs）。我们揭示 eCIRP 通过触发髓样细胞表达的受体-1（TREM-1）产生表达 ICAM-1 的中性粒细胞，并且这些 ICAM-1 中性粒细胞涉及 Rho GTPase 来促进 NETosis。rmCIRP 处理 BMDN 增加了表达 ICAM-1 的 BMDN 的频率，而 rmCIRP 处理的 TREM-1 BMDN 或 BMDN 的 TREM-1 抑制剂 LP17 预处理显著降低了表达 ICAM-1 的中性粒细胞的频率。rmCIRP 注射的小鼠或 LP17 处理的败血症小鼠的血液和肺部中表达 ICAM-1 的中性粒细胞的频率明显降低。与用 rmCIRP 处理的 WT 中性粒细胞相比，在存在肽基精氨酸脱亚氨酶 4（PAD4）抑制剂的情况下，ICAM-1 中性粒细胞或 WT 中性粒细胞与 WT 巨噬细胞的共培养减少了 TNF-α和 IL-6。与用 WT rmCIRP 处理的中性粒细胞相比，rmCIRP 处理的 ICAM-1 中性粒细胞的 NETs 数量减少。rmCIRP 诱导 BMDN 的 Rho 激活，而 ICAM-1 的阻断显著降低 Rho 激活。Rho 的抑制显著降低了 BMDN 中 rmCIRP 诱导的 NET 形成。TREM-1 在 eCIRP 介导的中性粒细胞中 ICAM-1 表达增加中起关键作用，通过 Rho 激活导致 NET 形成增加，从而加重炎症。
