Stroke is a leading cause of death in the United States, and those who survive stroke often live with serious long-term disabilities. With no neuroprotectants available to treat stroke, there is an urgent unmet need for new therapeutics that can recover lost function. The major type of stroke is focal cerebral ischemia, which is caused by a blocked artery in the brain. Primary brain injury occurs immediately after ischemic onset, and secondary injury is caused by reperfusion, when flow is restored to the blocked artery. Reperfusion injury is characterized by inflammation that involves the recruitment of macrophages (M?s) in the ischemic brain. Ischemic postconditioning (IPostC), or the mechanical interruption of reperfusion, is an emerging and promising neuroprotective strategy, but the underlying protective mechanisms of IPostC are largely unknown. Because reperfusion injury involves M?s, and IPostC interrupts reperfusion, the investigators hypothesize that M?s could be involved the protective effects of IPostC. In addition, M?s in the ischemic brain comprise both resident microglia-derived M?s (MiM?s) and blood monocyte-derived M?s (MoM?s), but their potential unique roles in IPostC have not been studied. Moreover, M?s are polarized into a pro-inflammatory M1 form and an anti-inflammatory M2 form, but how M1 and M2-polarized M?s are involved in IPostC has not been studied. The investigators will therefore use novel approaches to study how the inhibition of M?s and the alteration of M1/M2 polarization contribute to IPostC's protective effects. First, they have established a new IPostC model in mice that enable them to study M?s using various genetically-modified mouse strains and antibodies. Second, they will use the fluorescence-activated cell sorting (FACS) technique to identify, quantify and sort MoM?s from MiM?s. Third, they will use the cutting-edge high-throughput Fluidigm(r) BioMark HD system, a real-time PCR technique, to measure the gene expression of purified MoM?s and MiM?s. Pilot data have already shown that: (1) IPostC inhibited the accumulation of MoM?s, but had less effect on MiM?s; (2) exogenous MoM?s, but not resident MiM?s, had the strongest M1 and M2 gene expression; (3) MoM? depletion resulted in smaller infarctions in wild-type (WT) mice; (4) inhibition of MoM? recruitment in the ischemic brain by CCR2/CCL2 inhibitors or by CCR2 gene deficiency attenuated brain injury in WT and CCR2 gene knockout (KO) mice, respectively; (5) M1 polarization enlarged while M2 polarization inhibited infarct sizes; and (6) impairment of M2, specifically, resulted in larger infarctions in M? conditional IL4R? gene KO mice. Based on these preliminary findings, the investigators therefore propose 3 Specific Aims: (1) to study the effects of IPostC on MoM? and MiM? accumulation and polarization in acute ischemic brain injury; (2) to study whether inhibition of MoM? accumulation is critical for the protective effect of IPostC against stroke; an (3) to study the role of M? polarization in IPostC-mediated protective effects against stroke. The long-term goal is to advance the clinical translation of IPostC and M? strategies for stroke patients.
Macrophages, which are involved in inflammatory processes, may have a crucial role in ischemic postconditioning, an emerging neuroprotective strategy. Discovery of the underlying protective mechanisms related to monocyte-derived macrophages, specifically, could facilitate the clinical translation of ischemic postconditioning and macrophage inhibitive strategies.
|Wang, Peng; Xie, Rong; Cheng, Michelle et al. (2018) The mTOR cell signaling pathway is crucial to the long-term protective effects of ischemic postconditioning against stroke. Neurosci Lett 676:58-65|
|Yang, Jian; Liu, Cuiying; Du, Xiangnan et al. (2018) Hypoxia Inducible Factor 1? Plays a Key Role in Remote Ischemic Preconditioning Against Stroke by Modulating Inflammatory Responses in Rats. J Am Heart Assoc 7:|
|Xie, Rong; Li, Jinquan; Zhao, Heng (2018) The underlying mechanisms involved in the protective effects of ischemic postconditioning. Cond Med 1:73-79|
|Liu, Cuiying; Yang, Jian; Zhang, Chencheng et al. (2018) Analysis of long non-coding RNA expression profiles following focal cerebral ischemia in mice. Neurosci Lett 665:123-129|
|Zhou, Xin; Jiao, Zinan; Ji, Juling et al. (2017) Characterization of mouse serum exosomal small RNA content: The origins and their roles in modulating inflammatory response. Oncotarget 8:42712-42727|
|Liu, Cuiying; Zhang, Chencheng; Yang, Jian et al. (2017) Screening circular RNA expression patterns following focal cerebral ischemia in mice. Oncotarget 8:86535-86547|
|Li, Sijie; Hafeez, Adam; Noorulla, Fatima et al. (2017) Preconditioning in neuroprotection: From hypoxia to ischemia. Prog Neurobiol 157:79-91|
|Xiong, Xiaoxing; Gu, Lijuan; Wang, Yan et al. (2016) Glycyrrhizin protects against focal cerebral ischemia via inhibition of T cell activity and HMGB1-mediated mechanisms. J Neuroinflammation 13:241|
|Ji, Qiuhong; Ji, Yuhua; Peng, Jingwen et al. (2016) Increased Brain-Specific MiR-9 and MiR-124 in the Serum Exosomes of Acute Ischemic Stroke Patients. PLoS One 11:e0163645|
|Fan, Yifang; Xiong, Xiaoxing; Zhang, Yongming et al. (2016) MKEY, a Peptide Inhibitor of CXCL4-CCL5 Heterodimer Formation, Protects Against Stroke in Mice. J Am Heart Assoc 5:|
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