CD36 Mediates the Innate Host Response to β-Amyloid

Khoury, Joseph El; Moore, Kathryn J.; Means, Terry K.; Leung, Josephine H.; Terada, Kinya; Toft, Michelle; Freeman, Mason W.; Luster, Andrew D.

doi:10.1084/jem.20021546

Cited by 437 publications

(415 citation statements)

References 31 publications

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“…Both Webster et al (2001) and Das et al (2003) demonstrated A␤ phagocytosis in the presence of immune complexes in vitro; however, this result was only observed with the addition of fucoidan, which acted to block scavenger receptor binding. We and others have demonstrated the requirement for the B-class scavenger receptor CD36 participation in fA␤-stimulated microglia activation (Moore et al, 2002;Bamberger et al, 2003;El Khoury et al, 2003). The present study has established that CD36 is also essential for stimulation of fA␤ phagocytosis by microglia.…”

Section: Discussionsupporting

confidence: 48%

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Koenigsknecht

Landreth²

2004

J. Neurosci.

400

347

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Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar ␤-amyloid (fA␤)-containing plaques found in the brains of Alzheimer's disease (AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to A␤ deposits but can efficiently phagocytose A␤ fibrils and plaques in vitro.We report that exposure of microglia to fA␤ in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcR␥I and Fc␥RIII) or complement receptors. Microglia interact with fA␤ through a recently characterized A␤ cell surface receptor complex comprising the B-class scavenger receptor CD36, ␣ 6 ␤ 1 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fA␤-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a ␤ 1 integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fA␤ through a receptor-mediated, nonclassical phagocytic mechanism.

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Section: Discussionsupporting

confidence: 48%

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Koenigsknecht

Landreth²

2004

J. Neurosci.

400

347

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“…The class B scavenger receptor type 2, CD36, is involved in the Mu response to oxidized LDL [7,27] and mediates microglial and Mu responses to b-amyloid [28]. This scavenger receptor also recognizes anionic phospholipids [8], apoptotic cells [9], thrombospondin [29] and P. falciparum-infected erythrocytes [10].…”

Section: Discussionmentioning

confidence: 99%

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

et al. 2007

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The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)c pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARc pathway was demonstrated using transfection of a PPARc expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARc, and in peritoneal macrophages from PPARc-conditional null mice. We also show that CD36 induction by IL-13 via PPARc is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-D 12,14 -prostaglandin J 2 , an endogenous PPARc ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARc are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARc in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARc ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.Leukocyte signaling * These 2 authors contributed equally to this work. IntroductionThe innate immune system protects the host in the early phase of infection. Circulating monocytes and tissue macrophages (Mu) mediate much of this innate immune response [1]. The strategy of recognition in the innate response is mediated by the coordinated action of pathogen-associated molecular patterns and pattern recognition receptors. Scavenger receptors and mannose receptor are important pattern recognition receptors in monocytes/Mu [2,3]. The modulation of the expression of these receptors may be critical in the role of these cells in antigen processing, scavenging, and host defence against pathogens. Several members of the scavenger receptor family, including Mu class A scavenger receptors and CD36, have been identified as receptors for modified lipoproteins on Mu, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [4]. The scavenger receptor CD36, an 88-kDa integral membrane protein, is a class B scavenger receptor expressed on a wide variety of cells, in particular on monocytes and monocytederived Mu [5,6]. CD36 is known as a receptor for the uptake of oxidatively modified low-density lipoprotein (LDL) [7] and is also able to bind anionic phospholipid phosphatidylserine [8]. This scavenger receptor is implicated in the clearance of apoptotic cells [9]. Recently, McGilvray and colleagues [10] described a CD36-dependent nonopsonic phagocytosis of erythrocytes containing P. falciparum, by monocytes and culture-derived Mu, and a decrease in the parasiteinduced TNF secretion by monocytes/Mu. These processes were accentuated by CD36 up-regulation by peroxisome proliferator-acti...

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“…One possibility is that A␤ activates NADPH oxidase through the scavenger receptors RAGE (receptor for advanced glycation end product) or CD36 (El Khoury et al, 1996Khoury et al, , 2003Yan et al, 1996;Coraci et al, 2002). Activation of these receptors leads to increased ROS production, which is mediated by NADPH oxidase (Wautier et al, 2001;Bamberger et al, 2003;Abramov et al, 2004;Fuhrman et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

Park¹,

Anrather²,

Zhou³

et al. 2005

J. Neurosci.

221

229

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Overproduction of the amyloid ␤ (A␤) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of A␤ on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by A␤. Thus, the free-radical production and the associated alterations in vasoregulation induced by A␤ are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91 phox ). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91 phox . The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91 phox -containing NADPH oxidase is the critical link between A␤ and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

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CD36 Mediates the Innate Host Response to β-Amyloid

Cited by 437 publications

References 31 publications

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

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CD36 Mediates the Innate Host Response to β-Amyloid

Cited by 437 publications

References 31 publications

Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism

Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism

IL‐13 induces expression of CD36 in human monocytes through PPARγ activation

NADPH Oxidase-Derived Reactive Oxygen Species Mediate the Cerebrovascular Dysfunction Induced by the Amyloid β Peptide

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Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism