Hematoma resolution as a therapeutic target: the role of microglia/macrophages.
ABSTRACT No effective therapy is available for treating intracerebral hemorrhage (ICH). One of several key components of brain damage after ICH is the neurotoxicity of blood products. Within hours to days after ICH, extravasated erythrocytes in the hematoma undergo lysis, releasing cytotoxic hemoglobin, heme, and iron, thereby initiating secondary processes, which negatively influence the viability of cells surrounding the hematoma. To offset this process, phagocytic cells, including the brain's microglia and hematogenous macrophages, phagocytose and then process extravasated erythrocytes before lysis and subsequent toxicity occurs. Therefore, we hypothesize that a treatment that stimulates phagocytosis will lead to faster removal of blood from the ICH-affected brain, thus limiting/preventing hemolysis from occurring. CD36 is a well-recognized integral microglia/macrophage cell membrane protein known to mediate phagocytosis of damaged, apoptotic, or senescent cells, including erythrocytes. CD36 and catalase expression are regulated by peroxisome proliferator activated receptor-gamma agonists (eg, rosiglitazone). We demonstrate that peroxisome proliferator activated receptor-gamma agonist-induced upregulation of CD36 in macrophages enhances the ability of microglia to phagocytose red blood cells (in vitro assay), helps to improve hematoma resolution, and reduces ICH-induced deficit in a mouse model of ICH. The beneficial role of peroxisome proliferator activated receptor-gamma-induced catalase expression in the context of phagocytosis is also discussed. Proxisome proliferator activated receptor-gamma agonists could represent a potential treatment strategy for treatment of ICH.
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ABSTRACT: Microglia are the first line of immune defense against central nervous system (CNS) injuries and disorders. These highly plastic cells play dualistic roles in neuronal injury and recovery and are known for their ability to assume diverse phenotypes. A broad range of surface receptors are expressed on microglia and mediate microglial 'On' or 'Off' responses to signals from other host cells as well as invading microorganisms. The integrated actions of these receptors result in tightly regulated biological functions, including cell mobility, phagocytosis, the induction of acquired immunity, and trophic factor/inflammatory mediator release. Over the last few years, significant advances have been made towards deciphering the signaling mechanisms related to these receptors and their specific cellular functions. In this review, we describe the current state of knowledge of the surface receptors involved in microglial activation, with an emphasis on their engagement of distinct functional programs and their roles in CNS injuries. It will become evident from this review that microglial homeostasis is carefully maintained by multiple counterbalanced strategies, including, but not limited to, 'On' and 'Off' receptor signaling. Specific regulation of theses microglial receptors may be a promising therapeutic strategy against CNS injuries.Progress in neurobiology. 06/2014;
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ABSTRACT: This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood-brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer's disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.Fluids and barriers of the CNS. 01/2014; 11:18.
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ABSTRACT: Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36-deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild-type mice following ICH was increased, whereas the hematoma absorption in CD36(-/-) mice was decreased. CD36(-/-) mice also showed aggravated neurologic deficits and increased TNF-α and IL-1β expression levels. The phagocytic capacity of CD36(-/-) microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4(-/-) and MyD88(-/-) mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-α and IL-1β significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH.The Journal of Immunology 05/2014; · 5.36 Impact Factor