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. Author manuscript; available in PMC: 2009 Jun 26.
Published in final edited form as: J Neurochem. 2009 May;109(Suppl 1):126–132. doi: 10.1111/j.1471-4159.2009.05801.x

CD36: A multi-modal target for acute stroke therapy

Sunghee Cho 1,2, Eunhee Kim 1
PMCID: PMC2702148  NIHMSID: NIHMS106245  PMID: 19393018

Abstract

A role for CD36 in the pathogenesis of atherosclerosis, inflammation and lipid metabolism has been well-documented. However, little is known about the role of CD36 in cerebral ischemia. The intent of this review is to develop the concept that CD36, whose functions have been implicated in other pathological events, is a prototypic inflammatory receptor that contributes to the pathogenesis of cerebral ischemia. The importance of CD36 as a treatment target is indicated by the fact that many treatment strategies that are effective in experimental models of stroke exhibit little or no efficacy in clinical trials. The failure of clinical trials may be due to the use of animal models of stroke that do not reflect traditional risk factors for stroke in humans. The discussion will be focused on two risk factors, hyperlipidemia and diabetes, that modulate CD36 responses. Blocking the expression and function of CD36 by pharmacological or genetic means will provide insight not only toward identifying CD36 as a novel molecular target but also for developing effective therapeutic strategies to treat stroke victims. More importantly, coupling clinically relevant conditions with CD36-mediated ischemic injury may provide an appropriate animal model paradigm and develop a scientific understanding that could lead to clinical translational studies involving human subjects.

Introduction

Stroke is a leading cause of death and disability in the U.S. Despite a plethora of studies using animal models of stroke, treatment strategies that target a specific pathway and are effective in these models exhibit little or no efficacy during clinical trials. This may be attributed to the fact that unlike human clinical trials, animals used in preclinical evaluations of stroke may represent a more homogeneous population in terms of gender or age coupled with a relatively consistent degree of injury produced by established animal models. In addition, the pathology of stroke consists of multiple pro-death processes including necrosis, apoptosis, oxidative stress, vascular dysfunction, and pro-inflammatory responses. The interruption of a single pathway in well-controlled model systems thus may not be sufficient to overcome the multifactorial nature of stroke-induced injuries in the human population.

Another underlying issue hindering the development of treatment is the presence of predisposing clinical conditions frequently observed in stroke patients. Multiple cardio- and cerebral-vascular risk factors such as obesity, dyslipidemia, hypertension, insulin/glucose intolerance, and inflammation are associated with increased incidence of stroke either singly or in association with the clustering of other risk factors. More importantly, these additional clinical conditions may impact disease progression and outcomes of stroke-induced injury. Whereas less favorable outcomes are predicted in patients with predisposing clinical conditions, systematic inclusion of these risk factors in animal models may provide the next level of understanding of stroke pathology in clinical settings.

CD36, an 88 kDa glycoprotein, was originally described as platelet receptor glycoprotein and belongs to the class B scavenger receptor family. Existing knowledge of CD36 biology in other systems led us to formulate hypothesis that CD36 contributes to acute stroke pathophysiology. The review will discuss the evidence supporting the consideration of multimodal approaches and an inclusion of predisposing clinical conditions in an experimental model of stroke for an effective translation, particularly how CD36 fulfills both recommendations.

Multimodal approaches

To overcome the heterogeneous pathophysiology associated with stroke, multimodal approaches may be an appropriate strategy for treatment. Studies have shown that a combination of neuroprotective agents commonly used for stroke prevention effectively reduced post-stroke injury (Chen et al. 2004, Ding et al. 2005). Other promising multi-targeted approaches involve the transcriptional enhancement of genes that are responsible for pro-survival functions. Promoting histone acetylation using histone deacetylase inhibitors (Langley et al. 2005) or inhibitors of prolyl hydroxylase domain-containing proteins (Siddiq et al. 2005) resulting in protection from oxidative death and ischemic injury. This type of transcriptional approach has been suggested as a potential strategy for neuroprotection (Ratan et al. 2004).

Comparable to the above mentioned approaches, a strategy may be aimed at a single target that is implicated in multiple pathogenic downstream pathways. CD36 is a multifunctional receptor that is involved in numerous cellular processes. Many of these CD36-regulated processes are closely associated with pathological features frequently observed in neurodegenerative/neurological diseases.

Role of CD36 in acute stroke pathology

CD36 is a multifunctional receptor that is involved in inflammation, angiogenesis, lipid metabolism and atherosclerosis. It is expressed in various types of cells and tissues including microglia and astrocytes in the brain, monocytes/macrophages, platelets, microvascular endothelium, cardiac and skeletal muscle, adipocytes, dendritic cells, and epithelia of the retina, breast, and kidney. CD36 exhibits high affinity towards a wide variety of structurally distinct ligands, including oxidized or modified low density lipoprotein (oxLDL, mLDL), long-chain fatty acid (LCFA), thrombospondin (TSP) −1 and −2, fibrillar β-amyloid (fAβ), Plasmodium falciparum-parasitized erythrocytes, and membranes of cells undergoing apoptosis (for detailed review see (Febbraio et al. 2001, Febbraio & Silverstein 2007).

In spite of its low expression in the normal brain, CD36 expression is up-regulated following cerebral ischemia. Detailed immunohistochemical studies in the brain have shown that CD36 expression occurs mainly on CD11b+ microglia or infiltrated macrophages within the infarct territory throughout infarct development (Cho et al. 2005). CD36 staining is undetectable in neurons, whereas astrocytic expression is limited to the peri-infract area at the time the glial scar forms. The differential expression of CD36, either temporally or spatially, in the specific subsets of cells following ischemia suggests that CD36 may play diverse roles in stroke pathology. As a result of its expression in multiple cell types and a host of ligands produced in the ischemic brain, the activation of CD36 may have a significant impact on the progression and outcome of stroke (Figure 1). Targeting CD36 may permit concurrent mitigation of numerous pathogenic processes to achieve global neuroprotection.

Figure 1. A proposed multimodal strategy for stroke using CD36 as a target.

Figure 1

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A, The binding of thrombospondins (TSPs) elicits an anti-angiogenic signaling cascade that causes apoptosis of endothelial cells. By recognizing pathogen-associated molecular patterns of dying cells, CD36 is involved in innate immunity. In response to fibrillar Aβ (fAβ), CD36 mediates an innate host response. Foam cell formation by uptake of oxLDLs contributes to atherosclerotic lesion development. CD36 translocates long chain fatty acids (LCFA) across the plasma and mitochondrial membrane and involved in lipid metabolism. Ligands/receptor interactions markedly induce CD36 gene and protein expression in a feed forward manner and results in pathological consequences. B, Blocking CD36 by genetic or pharmacological means results in interruption of the feed forward loop, down-regulates CD36 pathways, and leads to global protection against pathological conditions such as stroke. L, ligands; Inh, Inhibitors

a. Angiogenesis

Angiogenesis plays a critical role in stroke outcome and recovery. Promotion of ischemia-induced angiogenesis, especially within the ischemic boundary, has been suggested as a therapeutic strategy to improve stroke outcome (Slevin et al. 2006).

Angiogenesis is tightly regulated by balancing the expression of factors that promotes as well as inhibits the formation of blood vessels. TSP-1 and 2 are extracellular matrix proteins and ligands for CD36. Binding of TSPs to CD36 mediates a signaling cascade that leads to endothelial cell apoptosis (Jimenez et al. 2000). The relevance of CD36 function in stroke pathology is its anti-angiogenic nature, which offsets compensatory angiogenesis-promoting cascades in response to tissue ischemia. With increased expression of CD36 and TSPs following ischemia (Lin et al. 2003, Hayashi et al. 2003, Cho et al. 2005), angiostatic signaling via excessive TSPs-CD36 interaction may contribute to the stroke pathology. A previous study showed that CD36 KO mice exhibited smaller infarct size and less behavior deficit (Cho et al. 2005). Whether the better ischemic outcome is attributed to the enhanced angiogenesis in the peri-infarct area remained to be investigated. By virtue of improving cerebral blood flow in the post-ischemic brain, blocking TSPs-CD36 interaction would be a potential strategy for stroke therapy.

b. Innate immunity

Recently, much attention has been given to the understanding of immune responses following cerebral ischemia. Isolated by the blood brain barrier, the brain has historically been considered an immune privileged organ. However, ischemia-induced blood brain barrier breakdown and subsequent exposure of CNS antigens to the infiltrating peripheral immune cells confirm the presence of all the components needed to trigger immune responses in the post-ischemic brain. The outcomes of the elicited immune responses are uncertain and may result in either protection (Ziv et al. 2007) or destruction (Gee et al. 2007). As the most primordial function in the organism, innate immunity serves to safeguard host tissue through the recognition of modified or oxidized phosphatidylcholine/serine motifs on the surface of apoptotic cells followed by subsequent removal of apoptotic and senescent cells (Hazen 2008). Triggered by tissue damage or infection by pathogenic or non-pathogenic microbes, the innate immune system appears to mediate ensuing inflammatory responses via a family of pattern recognition receptors. The receptors include toll-like receptors (TLRs) and CD36 which may recognize endogenous danger signals from damaged tissues (Matzinger 2002) or a host of structural motifs termed “pathogen-associated molecular pattern” for phagocytosis (Savill 1997).

The pathogenic roles of CD36 and TLR2 in cerebral ischemia have been independently reported. CD36 expression increases in the post-ischemic brain, and the targeted disruption of cd36 in mice reduces ischemic injury (Cho et al. 2005). Similarly, TLR2 expression is increased during ischemia and deletion of tlr2 results in reduced ischemic injury (Ziegler et al. 2007). A study showed that CD36 is a sensor of diacylated bacterial lipoprotein and a co-receptor for TLR2/6 (Hoebe et al. 2005). The closely shared function and physical association between CD36 and TLRs suggest that CD36 is involved in innate immune responses following cerebral ischemia. Targeting CD36 in an attempt to attenuate innate immune responses under pathological conditions may be a potential strategy for stroke therapy. Of particular note is that clearance of apoptotic cell bodies by phagocytosis, an essential function of scavenger receptors, may be an important process for tissue remodeling and wound healing after injury. Therefore, despite the potential damaging role of CD36 in acute ischemia, a role for CD36 in stroke recovery and remodeling process require further investigation.

c. Inflammation

Inflammation is a rapid and coordinated process in response to microbial infection. However, sterile inflammation, an inflammatory response in the absence of infection, also occurs in the setting of cerebral ischemia and trauma. Primary input to trigger sterile inflammatory responses is linked to the innate immune system through pattern recognition receptors (Mollen et al. 2006).

The pro-inflammatory nature of CD36 has been implicated in atherosclerosis (Febbraio et al. 2000), Alzheimer's disease (El Khoury et al. 2003), and Parkinson's disease (Su et al. 2007). In cerebral ischemia, CD36 mediates free radical generation and contributes to tissue injury in the post-ischemic brain (Cho et al. 2005). Using the cell permeable anti-oxidant peptide SS31 that down-regulates CD36 pathways, our laboratory demonstrated reduced injury size and GSH depletion in wild-type, but not in CD36 null mice after ischemia (Cho et al. 2007). A subsequent study reported a shift toward less pro-inflammatory state in the post-ischemic brain in the absence of CD36 and suggested that CD36 is a critical mediator to elicit pro-inflammatory responses following ischemia (Kim et al. 2008). Complementary to these studies, Kunz and colleagues reported reduced NF-κB activation in CD36 KO mice in the post ischemic brain (Kunz et al. 2008). The pro-inflammatory responses associated with generation of free radicals, cytokines, chemokines and foam cells through interaction between CD36/CD36 complex and ligands (oxLDL, fAβ) may be an integral part of many pathological processes and strategies may be aimed at attenuating injury-induced inflammation by targeting CD36.

d. Lipid metabolism

Yang and colleagues suggest a deleterious effect of long chain fatty acids on ischemic/reperfuision injury (Yang et al. 2007). In the cerebrospinal fluid from stroke patients, there is a significant increase in free fatty acids and increased lipid levels were shown to associate with poor ischemic outcomes (Pilitsis et al. 2003).

CD36 facilitates long chain fatty acids transfer across the plasma membrane (Abumrad et al. 1993). Because CD36 was also found on mitochondrial, an essential role of CD36 in fatty acid oxidation has been suggested (Bezaire et al. 2006). A recent study showed that enhanced fatty acid oxidation causes sub-cellular shuffling of CD36 to mitochondria (Benton et al. 2008). As reported in heart, hypoxia also induces the translocation of CD36 from the intracellular pool to the plasma membrane resulting in intracellular lipid accumulation (Chabowski et al. 2006). Intramyocardial lipid overload contributes to contractile dysfunction and ischemia-reperfusion injury (Korge et al. 2003). Although evidence of intracellular lipotoxicity in post-ischemic brain is currently lacking, it would be important to address whether elevated free fatty acids and intracellular lipid accumulation following cerebral ischemia is associated with CD36 and its subcellular localization. Whether this event negatively influences ischemic-reperfusion injury in the brain remains to be determined.

Clinical conditions that modulate CD36 expression and functions

The lack of translational efficacy of treatments used in rodents has prompted a reevaluation of experimental stroke models. In-depth analyses of critical issues including statistical power and reproducibility, statistical analysis, randomization, quality-control mechanisms, and bias on negative results have been recently addressed (Dirnagl 2006). Another relevant recommendation is inclusion of prevailing risk factors in the experimental models of stroke. Among predisposing clinical conditions associated with stroke patients, we will limit our discussion to hyperlipidemic and diabetic conditions because expression and function of CD36 changes in these conditions. Understanding how these conditions modulate ischemic outcome in relation to CD36 in a preclinical setting may provide a platform to develop strategies for effective translation.

a. Hyperlipidemia

Ligand-receptor interactions markedly induce CD36 gene and protein expression via peroxisome proliferators activated receptor (PPAR)-γ (Nagy et al. 1998), and promotes uptake of oxLDLs that leads to foam cell formation and development of atherosclerosis. A proatherogenic role for CD36 is further supported by the reduced lesion development in its absence (Febbraio et al. 2000, Guy et al. 2007, Moore et al. 2005). Generating excess lipid-based CD36 ligands in hyperlipidemic conditions may contribute to enhanced inflammation and may be linked to the pathology of cerebral ischemia. Our laboratory showed that hyperlipidemic mice showed larger infarct size, a disproportionally enlarged swelling, increased lipid content, formation of numerous foam cells (Figure 2), and heightened inflammation in the brain compared to the normolipidemic mice. Another intriguing finding from the study was that these foam cells were primarily localized in the peri-infarct area where post-ischemic inflammation predominates. Deletion of cd36 gene in these hyperlipidemic mice resulted in reduced infarct size and swelling, less foam cell formation, and reduced pro-inflammatory responses (Kim et al. 2008). The reversal of the pro-inflammatory phenotype in these mice suggests that CD36-mediated pathways are partly accountable for the exacerbation of ischemic injury in hyperlipidemic conditions.

Figure 2. Hyperlipidemia-promoted foam cell formation.

Figure 2

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Oil-red O staining in the ipsilateral side of normolipidemic (NL) and hyperlipidemic (HL) brain 3 days following ischemia. No foam cells were observed in the normolipidemic brain. On the contrary, there are numerous oil-red O stained foam cells in the penumbra from the hyperlipidmic brain. The lower panels show the higher magnification of the boxed areas. Scale bar, 500 μm

Another possible link between CD36 and lipids may be inferred from intervention studies with statins that show protection against cerebral ischemia (Sugiura et al. 2007). Although the protective effects are attributed to the pleiotropic actions of statins, the drugs attenuate CD36 expression/oxLDL uptake in inflammatory cells, increase cholesterol efflux, and decrease cholesterol ester accumulation (Fuhrman et al. 2002, Llaverias et al. 2004). Whether blocking the CD36-mediated lipid burden by statins or other pharmacological interventions is protective in hyperlipidemic conditions remains to be determined. However, the approach will confirm whether CD36-mediated excess lipid uptake contributes to the exacerbation of stroke-induced injury or not in hyperlipidemic conditions.

b. Diabetes

Studies show that 70% of new stroke victims were previously diagnosed with diabetes, occult diabetes, or were pre-diabetic (Ruiz-Velasco et al. 2004). Among non-diabetic patients with a history of a recent transient ischemic attack or ischemic stroke, impaired insulin sensitivity or insulin resistance was a prevalent condition (Argmann et al. 2005). There is a striking association between diabetes and the induction of CD36 expression. For instance, CD36 expression occurs in tissue or cells where diabetic complications prevail, such as the heart, microvascular endothelial cells, retinal pigment epithelium, and proximal renal tubular epithelial cells.

CD36 expression is increased in monocytes from type II diabetic patients (Kernan et al. 2003) and in the cardiac tissue of diabetic mice (Susztak et al. 2005). These studies are consistent with a report showing that impaired insulin signaling increases CD36 in macrophages isolated from ob/ob diabetic mice (Sampson et al. 2003). In addition to oxidative modification, LDLs are modified by glycation in the presence of high glucose. The resulting glycated-oxidized (glycoxidized) LDLs stimulate macrophage proliferation in a CD36-dependent manner and increase CD36 gene expression and cholesterol accumulation in THP-1 macrophages (Lam et al. 2004). By inference, the diabetic condition and/or hyperglycemia would be expected to exacerbate ischemic inflammation and injury via the augmented burden of CD36 ligands and function (Figure 3). Understanding the mechanism by which CD36 pathways are modulated in the experimental diabetic conditions will strengthen the link between the induction of CD36 and hyperglycemia and support the rationale for inclusion of the experimental diabetic conditions in the preclinical setting.

Figure 3. CD36 exacerbates ischemic injury in predisposing clinical conditions.

Figure 3

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Upon ischemia-reperfusion in normal condition, CD36 ligands such as free fatty acids (FFAs) and oxLDLs are generated. Interactions between CD36 and the liberated ligands generate reactive oxygen/nitrogen species and pro-inflammatory mediators, and contribute to ischemia-induced injury. Excessive ligands are generated in hyperlipidemic (FFAs, oxLDLs) and diabetic conditions (advanced glycated endproducts (AGEs), glycated-oxLDL(Glyc-oxLDL)). Enhanced receptor/ligand interactions further increase CD36 expression and the feed forward loop exacerbates ischemia-induced inflammation and injury. FFA, free fatty acid; AGE, advanced glycated end products; Glyc-oxLDL, glycated-oxidized LDL

Targeting CD36 for pharmacological intervention

Hexarelin, a member of the hexapeptide growth hormone-releasing peptides (GHRPs), binds to CD36 receptors (Demers et al. 2004). Treatment of mice with hexarelin or a structurally related analogue, EP80317, results in a marked decrease in atherosclerotic lesions (Marleau et al. 2005). Hexarelin exerts its protective effect by blocking CD36-mediated uptake of oxLDLs through binding site competition. Other promising antagonists against scavenger receptors are synthetically engineered nanoblockers that block the major scavenger receptors from oxLDLs uptake and thus prevent formation of foam cells (Chnari et al. 2006).

Besides targeting oxLDL binding sites, other approaches have been used to modulate CD36 expression or its downstream effects. Statins or antioxidants such as α-tocopherol, can reduce expression of CD36 and the uptake of oxLDLs into macrophages (Ricciarelli et al. 2000, Fuhrman et al. 2002). Another new class of antioxidants, SS peptides, significantly reduces reperfusion arrhythmia, myocardial stunning, and infarct size in vivo. The potency of the SS peptide antioxidants is attributed to their ability to concentrate within the inner mitochondrial membrane and inhibit the mitochondrial permeability transition, mitochondrial swelling, cytochrome c release, and apoptosis induced by lipid peroxides (Szeto 2006). Our laboratory has recently investigated the efficacy of SS31 on stroke. Treatment of mice with the SS31 peptide attenuated ischemia-induced GSH depletion in the cortex and reduced infarct size. By contrast, the protective effect of SS31 was abrogated in CD36 knock-out mice, indicating that its protective effect occurs at the level of CD36 via down regulating CD36-mediated pathways (Cho et al. 2007). The strong link between manifestations of oxidative stress and CD36 expression suggests that targeting CD36 may hold promise for a useful strategy treating acute ischemic stroke.

Summary

This review has provided evidence that CD36, functioning in the context of previously recognized pathological events, is linked to the pathology of cerebral ischemia including angiostasis, innate immunity and inflammation and lipid metabolism. In addition to these key functions, CD36 expression is closely associated with certain risk factors such as hyperlipidemia and diabetes. The concept that the predisposing clinical conditions modulate the extent of stroke-induced injury suggests an inclusion of experimental hyperlipidemic and diabetic conditions in animal models of stroke. Because CD36 is an inflammatory associated receptor that is at the crossroads of cardio- and cerebro-vascular diseases, intervening CD36-mediated inflammation and blocking its functions will provide insight whether the receptor serves as a novel molecular target to treat acute stroke.

Acknowledgements

This work was supported by NIH grant NHLBI RO1 HL082511 and The Burke Foundation.

Footnotes

Disclosure : Patent applications have been filed by Cornell Research Foundation, Inc. the technology (SS peptides) described in this article. Sunghee Cho is the co-inventor. Cornell Research Foundation, on behalf of Cornell University, has licensed the technology for further research and development to a commercial enterprise in which CRF has financial interests.

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