Fibrillar β-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia

Wilkinson, Brandy; Koenigsknecht-Talboo, Jessica; Grommes, Christian; Lee, C. Y. Daniel; Landreth, Gary E.

doi:10.1074/jbc.m600627200

Cited by 122 publications

(152 citation statements)

References 78 publications

(95 reference statements)

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“…We used in vivo and in vitro models of hyperlipidemia and oxidant stress to show CD36-dependent activation of all three Vavs in a manner that requires Src kinases (most likely Lyn). This is consistent with work from Landreth's group showing that engagement of CD36 on microglial cells by A␤ peptide induced Vav1 activation (21). Interestingly, whereas deletion of a single Vav (Vav1) led to modest inhibition of oxLDL uptake and foam cell formation, deletion of two Vavs (Vav1 and 3) led to nearly complete loss of foam cell formation (Fig.…”

Section: Discussionsupporting

confidence: 79%

“…Vavs have both unique and overlapping functions and can be activated by several pathways, including ligation of antigen receptors, integrins, growth factor receptors, and chemokine receptors (17,(23)(24)(25). In microglial cells Vav1 has been implicated in CD36-mediated responses to fibrillar A␤ amyloid peptides (21). Because Vav signaling impacts processes highly relevant to atherogenesis and involves pathways common to CD36 signaling, we hypothesized that Vavs could mechanistically link oxLDL-mediated CD36 signaling in macrophages to proatherogenic responses.…”

mentioning

confidence: 99%

“…In these capacities Vavs may regulate multiple processes, including NADPH oxidase-mediated generation of reactive oxygen species (19,20) and fission of endocytic vesicles from the plasma membrane (21,22). Vav1 is expressed exclusively in hematopoietic cells, whereas Vav2 and Vav3 are widely expressed.…”

mentioning

confidence: 99%

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Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Rahaman¹,

Swat

Febbraio

et al. 2011

Journal of Biological Chemistry

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Lipid-laden macrophages or "foam cells" are the primary components of the fatty streak, the earliest atherosclerotic lesion. Although Vav family guanine nucleotide exchange factors impact processes highly relevant to atherogenesis and are involved in pathways common to scavenger receptor CD36 signaling, their role in CD36-dependent macrophage foam cell formation remains unknown. The goal of the present study was to determine the contribution of Vav proteins to CD36-dependent foam cell formation and to identify the mechanisms by which Vavs participate in the process. We found that CD36 contributes to activation of Vav-1, -2, and -3 in aortae from hyperlipidemic mice and that oxidatively modified LDL (oxLDL) induces activation of macrophage Vav in vitro in a CD36 and Src family kinase-dependent manner. CD36-dependent uptake of oxLDL in vitro and foam cell formation in vitro and in vivo was significantly reduced in Vav null macrophages. These studies for the first time link CD36 and Vavs in a signaling pathway required for macrophage foam cell formation.Atherosclerosis is a complex inflammatory process driven in part by macrophage uptake of oxidized low density lipoproteins (oxLDL) 4 by scavenger receptors, such as CD36 and scavenger receptor A (1), leading to formation of lipid-laden "foam cells," the primary component of the earliest atherosclerotic lesions. Studies from our group and others demonstrated that CD36 accounts for a large proportion of foam cell formation in vitro and in vivo and that interruption of CD36 expression or downstream signaling blocks oxLDL uptake and limits experimental atherosclerosis in mice (2-9). CD36 is a multifunctional, multiligand transmembrane receptor expressed in a diverse array of cells including monocytes/macrophages, platelets, and adipocytes. Interestingly, CD36 deficiency is found in 0.5-1.0% of African and Asian populations (10, 11), and although atherosclerosis has yet to be studied in these groups, monocyte-derived macrophages collected from CD36-null individuals demonstrated 40% less binding and uptake of oxLDL compared with control individuals (12) with significant impairment of oxLDL-induced activation of NF-B and expression of proinflammatory genes (13). Numerous studies have revealed that CD36 acts as a signaling receptor, transmitting signals via Src family kinases (SFK) Lyn and Fyn, and MAP kinases JNK and p38, in response to multiple endogenous and exogenous ligands, including microbial pathogens, oxLDL, apoptotic cells, cell-derived microparticles, thrombospondin-related proteins, and amyloid peptides (14 -16). The precise molecular details, however, by which ligation of CD36 leads to recruitment and activation of a signaling complex are not fully understood. Identification of intracellular pathways required for oxLDL uptake and foam cell formation is vital for understanding the initiating stages of atherosclerosis and for designing novel targeted inhibitory agents. The studies outlined here demonstrate a critical role for Vav proteins in mediating CD36-depe...

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Section: Discussionsupporting

confidence: 79%

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confidence: 99%

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Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Rahaman¹,

Swat

Febbraio

et al. 2011

Journal of Biological Chemistry

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“…This leads to the downstream phosphorylation of p44/42 MAP kinases, and subsequent expression of TNF-α, MCP-1, MIP-1, MIP-2, IL-1β and reactive oxygen species (ROS). The vav guanine nucleotide exchange factor has recently been shown to link this signaling complex to the respiratory burst and phagocytosis in both monocytes and microglia (Figure 1b) (Wilkinson, Koenigsknecht-Talboo, Grommes, Lee, & Landreth, 2006). Similarly, fibrillar amyloid found in atheroma also elicits a CD36-dependent signaling cascade involving lyn and p44/42 MAP kinases, and ultimately CD36-dependent secretion of ROS and TNF-α (Stewart, et al, 2005).…”

Section: Cd36 Signalingmentioning

confidence: 93%

CD36: Implications in cardiovascular disease

Febbraio

Silverstein

2007

The International Journal of Biochemistry & Cell Biology

213

215

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CD36 is a broadly expressed membrane glycoprotein that acts as a facilitator of fatty acid uptake, a signaling molecule, and a receptor for a wide range of ligands, including apoptotic cells, modified forms of low density lipoprotein, thrombospondins, fibrillar beta-amyloid, components of gram positive bacterial walls and malaria infected erythrocytes. CD36 expression on macrophages, dendritic and endothelial cells, and in tissues including muscle, heart, and fat, suggest diverse roles, and indeed, this is truly a multifunctional receptor involved in both homeostatic and pathologic conditions. Despite an impressive increase in our knowledge of CD36 functions, in depth understanding of the mechanistic aspects of this protein remains elusive. This review focuses on CD36 in cardiovascular disease-what we know, and what we have yet to learn.

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“…A key signaling pathway through which Aβ activates NADPH oxidase in cerebral blood vessels involves CD36 (21), a critical innate immunity receptor that binds Aβ and is present in endothelial cells and microglia/macrophages (22,23). Genetic deletion of CD36 was shown to abrogate Aβ-induced vascular oxidative stress and cerebrovascular dysfunction in 3-mo-old mice overexpressing the Swedish mutation of APP (Tg2576) (21).…”

mentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

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Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions. T here is increasing evidence that alterations in the structure and function of cerebral blood vessels contribute to the brain dysfunction underlying Alzheimer's disease (AD) (1, 2). Whereas resting cerebral blood flow (CBF) is reduced early in course of AD (3, 4), the increase in CBF induced by brain activity (functional hyperemia), a vital mechanism matching the metabolic demands of active neurons with the delivery of nutrients through blood flow, is suppressed (5, 6). With disease progression, deposition of amyloid-β (Aβ) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), damages cerebrovascular cells, weakens vessel walls, and disrupts vascular function further (7). CAA also occurs independent of AD and has emerged as a frequent cause of brain hemorrhage, silent infarct, and cognitive impairment (8, 9).Studies in mice overexpressing mutated forms of the amyloid precursor protein (APP) have demonstrated that Aβ peptides, especially Aβ1-40, which accumulates preferentially in cerebral blood vessels, alter cerebrovascular function, resulting in vasoconstriction, impaired functional hyperemia, and inability of the endothelium to regulate vascular tone (10-12).These studies have raised the possibility that Aβ, in addition to damaging neurons and glia, also threatens the cerebral blood supply and increases the brain's susceptibility to hypoxia-ischemia (1, 13). Furthermore, considering that vascular transport is a key pathway for clearance of Aβ from the brain (14), these vascular alterations also may enhance the accumulation of Aβ in brain and cerebral blood vessels.Converging evidence indicates that Aβ exerts i...

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Fibrillar β-Amyloid-stimulated Intracellular Signaling Cascades Require Vav for Induction of Respiratory Burst and Phagocytosis in Monocytes and Microglia

Cited by 122 publications

References 78 publications

Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

Vav Family Rho Guanine Nucleotide Exchange Factors Regulate CD36-mediated Macrophage Foam Cell Formation

CD36: Implications in cardiovascular disease

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

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