Bexarotene Enhances Macrophage Erythrophagocytosis and Hematoma Clearance in Experimental Intracerebral Hemorrhage

被引：71

作者：

Chang, Che-Feng ^{[1
,2
]}

Massey, Jordan ^{[2
]}

Osherov, Artem ^{[2
]}

Angenendt da Costa, Luis Henrique ^{[3
]}

Sansing, Lauren H. ^{[2
]}

机构：

[1] Natl Taiwan Univ, Coll Med, Grad Inst Physiol, Taipei, Taiwan

[2] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA

[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Neurosci & Behav Sci, Sao Paulo, Brazil

来源：

STROKE | 2020年 / 51卷 / 02期

基金：

美国国家卫生研究院;

关键词：

bexarotene; cerebral hemorrhage; inflammation; macrophages; phagocytosis; ACTIVATED-RECEPTOR-GAMMA; PPAR-GAMMA; ALTERNATIVE ACTIVATION; NUCLEAR RECEPTORS; RESOLUTION; PHAGOCYTOSIS; MICE; RECRUITMENT; PROTECTS; TARGET;

D O I：

10.1161/STROKEAHA.119.027037

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and Purpose-Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain recovery after intracerebral hemorrhage (ICH). In the current study, we investigated the therapeutic effect of retinoid X receptor agonist, bexarotene, in facilitating erythrophagocytosis and neurobehavioral recovery in 2 mouse models of ICH. Methods-Bone marrow-derived macrophages and fluorescently labeled erythrocytes were used to study erythrophagocytosis in vitro with phenotypic changes quantified by gene expression. ICH was modeled in vivo using intrastriatal autologous blood and collagenase injection in mice with and without bexarotene treatment beginning 3 hours after ICH. In vivo phagocytosis, ability and hematoma clearance were evaluated by erythrophagocytosis assays, flow cytometry, and histological analysis. Neurological deficits and functional recovery were also quantified. Results-Bexarotene increased macrophage expression of phagocytosis receptors and erythrophagocytosis and reduced macrophage TNF (tumor necrosis factor) production in vitro. In vivo, bexarotene treatment enhanced erythrophagocytosis, reduced hematoma volume, and ultimately improved neurological recovery after ICH in 2 distinct models of ICH. Conclusions-Bexarotene administration is beneficial for recovery after ICH by enhancing hemorrhage phagocytosis, modulating macrophage phenotype, and improving functional recovery. Visual Overview-An online visual overview is available for this article.

引用

页码：612 / 618

页数：7

共 41 条

[1] Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage [J].

Askenase, Michael H. ;

Sansing, Lauren H. .

SEMINARS IN NEUROLOGY, 2016, 36 (03) :288-297

[2] Activation of RXR/PPARγ underlies neuroprotection by bexarotene in ischemic stroke [J].

Certo, Michelangelo ;

Endo, Yasuyuki ;

Ohta, Kiminori ;

Sakurada, Shinobu ;

Bagetta, Giacinto ;

Amantea, Diana .

PHARMACOLOGICAL RESEARCH, 2015, 102 :298-307

[3] Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage [J].

Chang, Che-Feng ;

Goods, Brittany A. ;

Askenase, Michael H. ;

Hammond, Matthew D. ;

Renfroe, Stephen C. ;

Steinschneider, Arthur F. ;

Landreneau, Margaret J. ;

Ai, Youxi ;

Beatty, Hannah E. ;

Angenendt da Costa, Luis Henrique ;

Mack, Matthias ;

Sheth, Kevin N. ;

Greer, David M. ;

Huttner, Anita ;

Coman, Daniel ;

Hyder, Fahmeed ;

Ghosh, Sourav ;

Rothlin, Carla V. ;

Love, J. Christopher ;

Sansing, Lauren H. .

JOURNAL OF CLINICAL INVESTIGATION, 2018, 128 (02) :607-624

[4] Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage [J].

Chang, Che-Feng ;

Wan, Jieru ;

Li, Qiang ;

Renfroe, Stephen C. ;

Heller, Nicola M. ;

Wang, Jian .

NEUROBIOLOGY OF DISEASE, 2017, 103 :54-69

[5] Translational Intracerebral Hemorrhage: a Need for Transparent Descriptions of Fresh Tissue Sampling and Preclinical Model Quality [J].

Chang, Che-Feng ;

Cai, Li ;

Wang, Jian .

TRANSLATIONAL STROKE RESEARCH, 2015, 6 (05) :384-389

[6] (-)-Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways [J].

Chang, Che-Feng ;

Cho, Suzy ;

Wang, Jian .

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2014, 1 (04) :258-271

[7] Intracerebral haemorrhage: current approaches to acute management [J].

Cordonnier, Charlotte ;

Demchuk, Andrew ;

Ziai, Wendy ;

Anderson, Craig S. .

LANCET, 2018, 392 (10154) :1257-1268

[8] ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models [J].

Cramer, Paige E. ;

Cirrito, John R. ;

Wesson, Daniel W. ;

Lee, C. Y. Daniel ;

Karlo, J. Colleen ;

Zinn, Adriana E. ;

Casali, Brad T. ;

Restivo, Jessica L. ;

Goebel, Whitney D. ;

James, Michael J. ;

Brunden, Kurt R. ;

Wilson, Donald A. ;

Landreth, Gary E. .

SCIENCE, 2012, 335 (6075) :1503-1506

[9] Bexarotene Modulates Retinoid-X-Receptor Expression and Is Protective Against Neurotoxic Endoplasmic Reticulum Stress Response and Apoptotic Pathway Activation [J].

Dheer, Yogita ;

Chitranshi, Nitin ;

Gupta, Veer ;

Abbasi, Mojdeh ;

Mirzaei, Mehdi ;

You, Yuyi ;

Chung, Roger ;

Graham, Stuart L. ;

Gupta, Vivek .

MOLECULAR NEUROBIOLOGY, 2018, 55 (12) :9043-9056

[10] Nuclear Receptors, RXR, and the Big Bang [J].

Evans, Ronald M. ;

Mangelsdorf, David J. .

CELL, 2014, 157 (01) :255-266

← 1 2 3 4 5 →