TREM (Triggering Receptor Expressed on Myeloid Cells)-1 Inhibition Attenuates Neuroinflammation via PKC (Protein Kinase C) delta/CARD9 (Caspase Recruitment Domain Family Member 9) Signaling Pathway After Intracerebral Hemorrhage in Mice

作者全名："Lu, Qin; Liu, Rui; Sherchan, Prativa; Ren, Reng; He, Wei; Fang, Yuanjian; Huang, Yi; Shi, Hui; Tang, Lihui; Yang, Shuxu; Zhang, John H.; Tang, Jiping"

作者地址："[Lu, Qin; Yang, Shuxu] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Neurosurg, Hangzhou, Peoples R China; [Ren, Reng; Fang, Yuanjian; Huang, Yi; Tang, Lihui] Zhejiang Univ, Affiliated Hosp 2, Dept Neurosurg, Sch Med, Hangzhou, Peoples R China; [Liu, Rui] Guizhou Prov Peoples Hosp, Dept Neurol, Guiyang, Peoples R China; [Lu, Qin; Liu, Rui; Sherchan, Prativa; Ren, Reng; He, Wei; Fang, Yuanjian; Huang, Yi; Shi, Hui; Tang, Lihui; Zhang, John H.; Tang, Jiping] Loma Linda Univ, Dept Physiol & Pharmacol, Loma Linda, CA 92350 USA; [Zhang, John H.] Loma Linda Univ, Dept Neurosurg, Loma Linda, CA 92350 USA; [Zhang, John H.] Loma Linda Univ, Dept Anesthesiol, Loma Linda, CA 92350 USA; [He, Wei] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Pharm, Hangzhou, Zhejiang, Peoples R China; [Shi, Hui] Chongqing Med Univ, Yongchuan Hosp, Dept Neurosurg, Chongqing, Peoples R China"

通信作者："Yang, SX (corresponding author), Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Neurosurg, Hangzhou, Peoples R China.; Tang, JP (corresponding author), Loma Linda Univ, Dept Physiol & Pharmacol, Loma Linda, CA 92350 USA."

来源：STROKE

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000653963600051

JCR分区：Q1

影响因子：8.3

年份：2021

卷号：52

期号：6

开始页：2162

结束页：2173

文献类型：Article

关键词：cerebral hemorrhage; inflammation; microglia; signaling pathway; triggering receptor expressed on myeloid cells 1

摘要："Background and Purpose: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke with high mortality and disability. Inflammatory response promotes secondary brain injury after ICH. TREM (triggering receptor expressed on myeloid cells)-1 is a key regulator of inflammation. The aim of this study was to evaluate the role of TREM-1 in neuroinflammatory response after ICH in mice. Methods: CD1 mice (n=275) were used in this study. Mice were subjected to ICH by autologous blood injection. TREM-1 knockout CRISPR was administered intracerebroventricularly to evaluate the role of TREM-1 after ICH. A selective TREM-1 inhibitor, LP17, was administered intranasally 2 hours after ICH. To elucidate TREM-1 signaling pathway, CARD9 (caspase recruitment domain family member 9) activation CRISPR was administered with LP17 and TREM-1 activating anti-mouse TREM-1 monoclonal antibody (mAb) was administered with Rottlerin, a specific PKC (protein kinase C) delta inhibitor. Lastly, to evaluate the role of HMGB1 (high-mobility group box 1) in TREM-1 mediated microglia activation, glycyrrhizin, an inhibitor of HMBG1 was administered with TREM-1 activating mAb. Neurobehavioral test, brain water content, Western blot, immunofluorescence staining, and coimmunoprecipitation was performed. Results: TREM-1 knockout reduced ICH-induced neurobehavioral deficits and neuroinflammatory response. The temporal expression of HMGB1, TREM-1, PKC delta, and CARD9 increased after ICH. TREM-1 was expressed on microglia. Intranasal administration of LP17 significantly decreased brain edema and improved neurobehavioral outcomes at 24 and 72 hours after ICH. LP17 promoted M2 microglia polarization and reduced proinflammatory cytokines after ICH, which was reversed with CARD9 activation CRISPR. TREM-1 mAb increased neurobehavior deficits, proinflammatory cytokines, and reduced M2 microglia after ICH, which was reversed with Rottlerin. HMBG1 interaction with TREM-1 increased after ICH, and glycyrrhizin reduced neuroinflammation and promoted M2 microglia which was reversed with TREM-1 mAb. Conclusions: This study demonstrated that TREM-1 enhanced neuroinflammation by modulating microglia polarization after ICH, and this regulation was partly mediated via PKC delta/CARD9 signaling pathway and increased HMGB1 activation of TREM-1."

基金机构：National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS101284]

基金资助正文：This work was supported by the National Institutes of Health (NS101284) to J. Tang.