CD36/Fatty Acid Translocase, An Inflammatory Mediator, Is Involved in Hyperlipidemia-Induced Exacerbation in Ischemic Brain Injury

Abstract

Hyperlipidemia with accompanying increase in peripheral inflammation is a risk factor for stroke. The effect of excess lipids on strokeinduced injury and the mechanism by which lipid-mediated inflammatory responses contribute to stroke are not known. We investigated these uncertainties by subjecting normal and hyperlipidemic mice to transient middle cerebral artery occlusion, followed by measurement of stroke severity and inflammatory response. Infarct size, swelling, and lipid contents were significantly increased in the high-fat fed ApoE knock-out mice, as was the expression of the inflammatory mediators CD36 and monocyte chemoattractant protein 1 (MCP-1) in the brain and periphery. Furthermore, the hyperlipidemic mice exhibited numerous foam cells, a probable cause of increased swelling and postischemic inflammation, in the peri-infarct area. Genetic deletion of cd36 in the hyperlipidemic condition reduced proinflammatory chemokine/receptor and cytokines (MCP-1, CC chemokine receptor 2, and interleukins 1␤ and 6), in the brain 6 h after ischemia. The reduced proinflammatory response also resulted in smaller ischemic injury, less swelling, and fewer foam cells at 3 d after ischemia. The results show that hyperlipidemia-induced inflammation is a negative factor for stroke outcomes and indicate that downregulating CD36 may be an effective therapeutic strategy for reducing the impact of stroke in hyperlipidemic subjects.

Scavenger Receptor Class-A Has a Central Role in Cerebral Ischemia–Reperfusion Injury

“…We observed in this study that SR-A deficiency significantly reduced infarction after cerebral I/R, suggesting that SR-A, that is expressed on the microglia and Mato cells, could mediate pathophysiological response to cerebral I/R injury. Cho et al (2005) (Kim et al, 2008;Kunz et al, 2008) recently reported that the class B scavenger receptor (CD36) has a role in brain ischemic injury. CD36 is a membrane glycoprotein that is found on many cell types, including platelets, endothelial cells, macrophages, adipocytes, and microglia, and has been implicated in a host of normal and disease processes (Silverstein and Febbraio, 2009).…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…The hyperlipidemic mice had higher CD36 expression in peripheral macrophages prior to stroke and had li pi d-la de n f oa m ce ll s in t h e p o s t s t r o k e b r a i n . Hyperlipidemic mice with targeted disruption of CD36 showed a reversal of the hyperlipidemia-associated phenotype in the brain (i.e., reduced infarct size, less foam cell formation, and less proinflammatory cytokine and chemokine expression) [152]. A subsequent study revealed the involvement of CD36 expression in peripheral mononuclear phagocytes and CNS for hyperlipidemia-induced exacerbation of infarct volume and brain edema.…”

“…CD36 is highly expressed in microglia, monocytes/macrophages, microvascular endothelial cells, platelets, and epithelial cells and it regulates inflammation, innate immunity, angiogenesis, and lipid metabolism through interactions with lipid and nonlipid-based ligands [151]. Several studies demonstrated that CD36 expression is upregulated in the ischemic brain [152], and that CD36 is involved in stroke-induced inflammation and injury [101,[152][153][154]. Despite the detrimental effects of CD36 in an acute ischemic setting, CD36-dependent phagocytosis was associated with functional benefit in neonatal stroke [155].…”

“…These conditions are often associated with the exacerbation of ischemic outcomes and are predictive of worse recovery [186]. The inclusion of hyperlipidemia and diabetes in animal models of stroke has demonstrated that these conditions modulate postischemic inflammatory responses and lesion development [101,152,187,188]. In addition, increased inflammatory factors such as cytokines, chemokines, and adhesion molecules in peripheral monocytes/macrophages in these conditions suggest that peripheral immune status modulates CNS injury.…”

CD36 is Involved in Astrocyte Activation and Astroglial Scar Formation

“…Substantial evidence suggests a role for CD36 in stroke pathology associated with inflammation (Cho et al, 2005;Cho and Kim, 2009). Ischemic stroke produces several CD36 ligands including oxidized/modified low-density lipoprotein and thrombospondins (Kim et al, 2008;Lin et al, 2003;Qin et al, 2011). We previously reported that CD36 contributes to free radical generation in the postischemic brain and that its deficiency ameliorates stroke-induced inflammation and injury (Cho et al, 2005;Cho and Kim, 2009;Kim et al, 2008).…”