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PubMed1989

Intercellular adhesion molecule-1 is an endothelial cell adhesion receptor for Plasmodium falciparum.

The primary event in the pathogenesis of severe malaria in Plasmodium falciparum infection is thought to be adherence of trophozoite- and schizont-infected erythrocytes to capillary endothelium, a process called sequestration. Identifying the endothelial molecules used as receptors is an essential step in understanding this disease process. Recent work implicates the membrane glycoprotein CD36 (platelet glycoprotein IV; refs 2-5) and the multi-functional glycoprotein thrombospondin as receptors. Although CD36 has a widespread distribution on microvascular endothelium, it may not be expressed on all capillary beds where sequestration occurs, especially in the brain. The role of thrombospondin in cell adhesion, in vitro or in vivo, is less certain. We have noticed that some parasites bind to human umbilical-vein endothelial cells independently of CD36 or thrombospondin. To screen for alternative receptors, we have developed a novel cell-adhesion assay using transfected COS cells, which confirms that CD36 is a cell-adhesion receptor. In addition, we find that an endothelial-binding line of P. falciparum binds to COS cells transfected with a complementary DNA encoding intercellular adhesion molecule-1. As this molecule is widely distributed on capillaries and is inducible, this finding may be relevant to the pathogenesis of severe malaria.

Antibodies, Monoclonal↗
PubMed2001

c-Jun N-terminal kinase activation is required for the inhibition of neovascularization by thrombospondin-1.

Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis that acts directly on endothelial cells via the CD36 surface receptor molecule to halt their migration, proliferation, and morphogenesis in vitro and to block neovascularization in vivo. Here we show that inhibitory signals elicited by TSP-1 did not alter the ability of inducers of angiogenesis to activate p42 and p44 mitogen-activated protein kinase (MAPK). Rather, TSP-1 induced a rapid and transient activation of c-Jun N-terminal kinases (JNK). JNK activation by TSP-1 required engagement of CD36, as it was blocked by antagonistic CD36 antibodies and stimulated by short anti-angiogenic peptides derived from TSP-1 that act exclusively via CD36. TSP-1 inhibition of corneal neovascularization induced by bFGF was severely impaired in mice null for JNK-1, pointing to a critical role for this stress-activated kinase in the inhibition of neovascularization by TSP-1.

Angiogenesis Inhibitors↗
PubMed1999

Activation of the GP IIb-IIIa complex induced by platelet adhesion to collagen is mediated by both alpha2beta1 integrin and GP VI.

alpha2beta1 integrin, CD36, and GP VI have all been implicated in platelet-collagen adhesive interactions. We have investigated the role of these glycoproteins on activation of the GP IIb-IIIa complex induced by platelet adhesion to type I fibrillar and monomeric collagen under static conditions. In the presence of Mg2+, platelet adhesion to fibrillar collagen induced activation of the GP IIb-IIIa complex and complete spreading. Anti-alpha2beta1 integrin and anti-GP VI antibodies inhibited the activation of the GP IIb-IIIa complex by about 40 and 50%, respectively, at 60 min although minimal inhibitory effects on adhesion were seen. Platelet spreading was markedly reduced by anti-alpha2beta1 integrin antibody. The combination of anti-alpha2beta1 integrin with anti-GP VI antibody completely inhibited both platelet adhesion and activation of the GP IIb-IIIa complex. Anti-CD36 antibody had no significant effects on platelet adhesion, spreading, and the activation of the GP IIb-IIIa complex at 60 min. Aspirin and the thromboxane A2 receptor antagonist SQ29548 inhibited activation of the GP IIb-IIIa complex about 30% but had minimal inhibitory effect on adhesion. In the absence of Mg2+, there was significant activation of the GP IIb-IIIa complex but minimal spreading was observed. Anti-GP VI antibody completely inhibited adhesion whereas no effect was observed with anti-alpha2beta1 integrin antibody. Anti-CD36 antibody partially inhibited both adhesion and the activation of the GP IIb-IIIa complex. Platelet adhesion to monomeric collagen, which requires Mg2+ and is exclusively mediated by alpha2beta1 integrin, resulted in partial activation of the GPIIb-IIIa complex and spreading. No significant effects were observed by anti-CD36 and anti-GP VI antibodies. These results suggest that both alpha2beta1 integrin and GP VI are involved in inside-out signaling leading to activation of the GP IIb-IIIa complex after platelet adhesion to collagen and generation of thromboxane A2 may further enhance expression of activated GP IIb-IIIa complexes.

Animals↗
PubMed2005

Plasmodium falciparum antigenic variation: relationships between in vivo selection, acquired antibody response, and disease severity.

BACKGROUND: Variant surface antigens (VSA) on Plasmodium falciparum-infected erythrocytes are potentially important targets of immunity to malaria. We previously identified a VSA phenotype--VSA with a high frequency of antibody recognition (VSA(FoRH))--that is associated with young host age and severe malaria. We hypothesized that VSA(FoRH) are positively selected by host molecules such as intercellular adhesion molecule 1 (ICAM1) and CD36 and dominate in the absence of an effective immune response. Here, we assessed, in 115 Kenyan children, the potential role played by in vivo selection pressures in either favoring or selecting against VSA(FoRH) among parasites that cause malaria. METHODS: We tested for associations between VSA(FoRH) and (1) the repertoire of VSA antibodies carried by children at the time of acute malaria and (2) polymorphisms in ICAM1 (K29M) and CD36 (T188G) that could potentially reduce the positive selection of VSA(FoRH). RESULTS: An expected negative association between VSA antibody repertoire and VSA(FoRH) was observed in children with nonsevere malaria. However, this association did not extend to children with severe malaria, many of whom apparently had well-developed VSA antibody responses despite being infected by parasites expressing VSA(FoRH). There was no evidence for involvement of CD36 or ICAM1 in positive selection of VSA(FoRH). On the contrary, a weak positive association between carriage of the CD36 (T188G) allele and VSA(FoRH) was observed in children with severe malaria. CONCLUSION: The association between the VSA(FoRH) parasite phenotype and severe malaria cannot be explained simply in terms of the total repertoire of VSA antibodies carried at the time of acute disease.

Amino Acid Substitution↗
PubMed2004

Effect of tacrolimus on the expression of macrophage scavenger and nuclear hormone receptors in THP-1-derived human macrophages.

BACKGROUND: Data indicate that tacrolimus and cyclosporine A (CsA) differentially affect the risk of atherosclerosis. The results of our recent in vitro studies of clinically relevant CsA concentrations demonstrated the modulation of macrophage scavenger receptors (MSRs) involved in atherogenesis. This work evaluated the effects of clinically relevant tacrolimus concentrations on the expression of the MSR genes CD36 and CD68, SR-A and SR-BII, lectin-like oxidized low-density lipoprotein receptor-1, the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR)gamma and liver-X-receptor-alpha, and the cholesterol efflux pump ABCA1 in the in vitro human THP-1 macrophage model. METHODS: The cells were cultured and differentiated into macrophages. Macrophages were treated with the tacrolimus to assess gene expression in a time-dependent (1, 2, 4, 8, and 24 hr) and dose-dependent (concentrations [micrograms/liter] corresponding to the trough [15], peak [30], and 4 x peak [120]) manner using reverse-transcriptase polymerase chain reactions. The gene expression levels of interest were normalized to GAPDH expression in each sample to provide semiquantitative reverse-transcriptase polymerase chain reaction results. Additional immunoblotting studies demonstrated protein expression of CD36, PPARgamma, and ABCA1. RESULTS.: The gene expression of CD36, SR-BII, and lectin-like oxidized low-density lipoprotein receptor-1 were down-regulated, and ABCA1 was up-regulated. CD68, SR-AI, liver-X-receptor-alpha, and PPARgamma were regulated in a dose-dependent manner. Protein expression of CD36 was down-regulated, and PPARgamma and ABCA1 were relatively unchanged. CONCLUSIONS: Tacrolimus seems to regulate MSRs, nuclear hormone receptors, and ABCA1 in THP-1 macrophages. These results differ from previous findings with CsA and may provide insight into the mechanisms of posttransplant atherosclerosis.

ATP Binding Cassette Transporter 1↗
PubMed2006

Direct association of a promoter polymorphism in the CD36/FAT fatty acid transporter gene with Type 2 diabetes mellitus and insulin resistance.

AIMS: The membrane-bound fatty acid transporter CD36/FAT may play a role in disturbed fatty acid handling as observed in the metabolic syndrome and Type 2 diabetes mellitus (T2DM). Genetic variation in the CD36 gene may contribute to the aetiology of diabetes. METHODS: A population-based cohort in the Netherlands [age > 40 years and body mass index (BMI) > 25 kg/m2] of 675 subjects was phenotyped with respect to glucose metabolism with an oral glucose tolerance test and was genotyped for a known 478C-->T substitution and a C/T snp in the upstream promoter region (rs1527479) in the CD36 gene. RESULTS: T2DM was more prevalent in the TT genotype than in the CC genotype. This was most pronounced in women and in subjects with a high BMI (BMI > 27 kg/m2). In addition, within the group of diabetic patients, the TT genotype was commoner in subjects with increased homeostasis model assessment (HOMA) index for insulin resistance. The 478C-->T substitution, previously found in the Japanese population, was not found in our caucasian population. CONCLUSIONS: This is the first study to show a direct association of a CD36 snp with T2DM. Moreover, within the diabetic subjects, this CD36 snp was associated with insulin resistance (HOMA index).

Aged↗
PubMed2002

Cytoadherence of malaria-infected red blood cells involves exposure of phosphatidylserine.

Phosphatidylserine (PS) is a membrane phospholipid which in intact cells is exclusively localized in the inner leaflet of the lipid bilayer. However, once cells undergo apoptosis or oxidative stress, PS molecules are exposed on the external surface of the cells and this contributes to their adherence to macrophages or endothelial cells. PS exposure on Plasmodium falciparum-infected red cells was determined by flow cytometry using fluorescein-labeled annexin V, which specifically binds to PS. Involvement of exposed PS in the adherence of malaria-infected red cells to endothelial cells was examined by in vitro cytoadherence assays. Infected cells exposed PS on their surface as the intracellular parasites matured to trophozoite and schizont stages. Adherence of malaria-infected cells to CD36, CD36-expressing Chinese hamster ovary cells, thrombospondin, and C32 amelanotic melanoma cells was inhibited by annexin V, whereas ICAM-1- and chondroitin sulfate A-mediated binding was not. Further, PS liposomes and glycerophosphorylserine, but not phosphatidylcholine liposomes and glycerophosphorylcholine, inhibited the binding of infected cells to CD36 and thrombospondin. In conclusion, these results demonstrate that PS exposed on the surface of malaria-infected red cells contributes, in part, to the adherence of P. falciparum-parasitized red cells to CD36 and thrombospondin.

Animals↗
PubMed2005

Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice.

OBJECTIVE: Histone acetylation has been shown to be involved in expression of a restricted set of cellular genes including various proinflammatory molecules. We aimed to investigate the relationship between histone acetylation and atherosclerosis. METHODS AND RESULTS: In low-density lipoprotein (LDL) receptor-deficient (Ldlr(-/-)) mice fed an atherogenic diet for 4 or 8 weeks, trichostatin A (TSA), a specific histone deacetylase inhibitor, exacerbated atherosclerosis without alteration on plasma lipid profiles. When we assayed the effects of TSA on expressions of oxidized LDL (oxLDL) receptors on RAW264.7 macrophage, we found that TSA increased CD36 mRNA and protein, as well as cell surface expression of CD36. TSA also increased acetylation at the CD36 promoter region. The uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine percholate (Dil)-labeled oxLDL was enhanced in RAW264.7 macrophage by TSA. Furthermore, TSA treatment increased CD36 mRNA expression in aorta, and SRA, tumor necrosis factor (TNF)-alpha, and vascular cell adhesion molecule-1 (VCAM-1) were also elevated, whereas IL-6 and IL-1beta expressions were decreased. CONCLUSIONS: Our findings suggest that histone acetylation could play some role in atherogenesis by modulating expressions of oxLDL receptor and some proatherogenic genes. Therefore, our results indicate that increased histone acetylation may affect the progress of atherosclerosis.

Acetylation↗
PubMed2002

Src-family kinase signaling modulates the adhesion of Plasmodium falciparum on human microvascular endothelium under flow.

The pathogenicity of Plasmodium falciparum is due to the unique ability of infected erythrocytes (IRBCs) to adhere to vascular endothelium. We investigated whether adhesion of IRBCs to CD36, the major cytoadherence receptor on human dermal microvascular endothelial cells (HDMECs), induces intracellular signaling and regulates adhesion. A recombinant peptide corresponding to the minimal CD36-binding domain from P falciparum erythrocyte membrane protein 1 (PfEMP1), as well as an anti-CD36 monoclonal antibody (mAb) that inhibits IRBC binding, activated the mitogen-activated protein (MAP) kinase pathway that was dependent on Src-family kinase activity. Treatment of HDMECs with a Src-family kinase-selective inhibitor (PP1) inhibited adhesion of IRBCs in a flow-chamber assay by 72% (P <.001). More importantly, Src-family kinase activity was also required for cytoadherence to intact human microvessels in a human/severe combined immunodeficient (SCID) mouse model in vivo. The effect of PP1 could be mimicked by levamisole, a specific alkaline-phosphatase inhibitor. Firm adhesion to PP1-treated endothelium was restored by exogenous alkaline phosphatase. In contrast, inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) and p38 MAP kinase pathways had no immediate effect on IRBC adhesion. These results suggest a novel mechanism for the modulation of cytoadherence under flow conditions through a signaling pathway involving CD36, Src-family kinases, and an ectoalkaline phosphatase. Targeting endothelial ectoalkaline phosphatases and/or signaling molecules may constitute a novel therapeutic strategy against severe falciparum malaria.

Alkaline Phosphatase↗
PubMed2001

Fetal hemoglobin in sickle cell anemia: relationship to erythrocyte adhesion markers and adhesion.

To assess whether fetal hemoglobin (HbF) modulates the adhesion of sickle erythrocytes to endothelium, children with homozygous sickle cell anemia (SS disease) were studied, using this physiologically crucial period to evaluate the relationships between HbF and the major erythrocyte adhesion markers. The mean level of CD36(+) erythrocytes was 2.59% +/- 2.15% (+/- SD, n = 40) with an inverse relationship between CD36 positivity and F cells (R = -0.76, P < .000 00 002). In univariate analyses, significant correlations with various hematologic parameters and age were noted. Multiple regression analyses, however, revealed a relationship solely with F cells. Minimal levels of very late activation antigen-4(+) (VLA4(+)) erythrocytes (0.31% +/- 0.45%, n = 40) with relationships similar to those noted for CD36(+) cells were also observed. The subpopulation of strongly adhesive stress reticulocytes was further assessed, using CD71 as their marker. The mean level of CD71(+) erythrocytes was 5.81% +/- 4.21%, with statistical correlates in univariate and multivariate analyses similar to those discussed above. When adhesion ratios were evaluated, inverse correlations were noted between basal and plasma-induced adhesion and F-cell numbers (R = -0.54, P < .0005; R = -0.53, P < .0006, n = 39). In addition, in analyses where basal or plasma-induced adhesion was the dependent variable and the independent variables included F cells and the various adhesion-related parameters, significant relationships solely with F cells were noted. The results demonstrate that SS patients with higher levels of F cells have concomitant decreases in the numbers of CD36(+), VLA4(+), and CD71(+) erythrocytes and that these findings translate into less adherent erythrocytes. These findings extend knowledge regarding the protective effects of HbF in the pathophysiology of sickle cell disease.

Adolescent↗
PubMed2000

Genetic analysis of cardiovascular risk factor clustering in spontaneous hypertension.

The SHR is the most widely studied animal model of hypertension. In this strain, as in many humans with essential hypertension, increased blood pressure has been reported to cluster with other risk factors for cardiovascular disease, including insulin resistance and dyslipidemia. However, the genetic mechanisms that mediate this clustering of risk factors for cardiovascular disease or the hypertension "metabolic syndrome" remain poorly understood. In the current studies, we have demonstrated (1) that a gene or genes responsible for a whole spectrum of cardiovascular risk factors mapped to a limited segment of the centromeric region of rat chromosome 4, (2) that a spontaneous deletion in the gene for Cd36 that encodes a fatty acid transporter and is located directly at the peak of QTL linkages on chromosome 4 has been indirectly linked to the transmission of insulin resistance, defective fatty acid metabolism, and increased blood pressure, and (3) based on complementation analysis in two transgenic lines expressing wild-type Cd36 on the genetic background of the SHR strain harboring the deletion variant of Cd36, we have established that defective Cd36 can be a determinant of disordered fatty acid metabolism, glucose intolerance, and insulin resistance in spontaneous hypertension.

Animals↗
PubMed1997

Receptor-specific adhesion and clinical disease in Plasmodium falciparum.

One important factor in the virulence of infections with Plasmodium falciparum is the adherence of infected erythrocytes to small vessel endothelium. In infections that lead to serious, life-threatening disease accumulation of large numbers of infected cells in particular organs is thought to lead to organ dysfunction or failure. This is of particular relevance when the affected organ is the brain, leading to the development of cerebral malaria. Many different endothelial receptors for infected red blood cells have been identified. Some receptors such as CD36 and thrombospondin are used by all parasite isolates, whereas others such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule (VCAM) are used by a subset of field and laboratory isolates. While it has been speculated that the ability to bind or affinity of binding to a particular endothelial receptor may be related to the pattern of disease, only studies with limited numbers of patients have been carried out to date and these have been in general inconclusive. Here we have taken parasite isolates from 150 patients with defined clinical syndromes as well as isolates from 50 healthy but parasitized community controls and quantitatively assessed their binding to purified endothelial receptors in vitro. Our results show that disregarding the level of adhesion, all parasites bind to CD36, most bind to ICAM-1, few bind to VCAM, and almost none bind to E-selectin. In assessing the degree of binding we show that 1) binding to all receptors was reduced in parasites taken from severely anemic patients; 2) binding to CD36 is identical in parasites from cerebral malaria patients and community controls but slightly elevated in parasites from nonsevere cases; and 3) binding to ICAM-1 is highest in cerebral malaria patients. Because rosette formation by uninfected cells has also been a phenotype associated with disease severity and one that may interfere in vitro with receptor binding, we also assessed rosette formation in all isolates. In this study the highest level of rosette-forming parasites was found in the anemic group and not the cerebral malaria group. Stratifying the data for the frequency of rosette formation showed that the above results were not significantly altered by this phenomenon. Our data are not consistent with a role for binding to CD36 in the development of severe disease but show an association between the degree of binding to ICAM-1 and clinical illness in nonanemic patients.

Anemia↗
PubMed1999

Cytoadherence characteristics of Plasmodium falciparum-infected erythrocytes from Malawian children with severe and uncomplicated malaria.

Cytoadherence of Plasmodium falciparum-infected erythrocytes to the microvascular endothelium is believed to be a key factor in the development of cerebral malaria. Erythrocyte rosette formation has been correlated with malaria severity in studies from east and west Africa. We cultured fresh isolates from Malawian children with severe (n = 76) or uncomplicated (n = 79) malaria to pigmented trophozoite stage and examined rosette formation and adherence to CD36, intercellular adhesion molecule-1 (ICAM-1), chondroitin sulfate A (CSA), and thrombomodulin (TM). Most (126 of 148) isolates bound to CD36, and 76 of 136 bound to ICAM-1. Fewer bound to CSA (40 of 148) or TM (23 of 148). After controlling for parasitemia, there was an inverse association between binding to CD36 (P = 0.004) or ICAM-1 (P = 0.001) and disease severity. Parasites from children with severe malaria anemia bound least to CD36, whereas ICAM-1 binding was lowest in children with cerebral malaria. There was no difference in rosette formation between any of the groups. In Malawian children, there was no evidence of a positive association between adherence to any of the receptors examined and disease severity. The negative association found raises the possibility that adherence to certain receptors could instead be an indicator of a less pathogenic infection.

Anemia↗
PubMed2000

Macrophage receptors responsible for distinct recognition of low density lipoprotein containing pyrrole or pyridinium adducts: models of oxidized low density lipoprotein.

Oxidation of low density lipoproteins (LDL) induced by incubation with Cu(2+) ions results in the formation of a heterogeneous group of aldehydic adducts on lysyl residues (Lys) of apolipoprotein B (apoB) that are thought to be responsible for the uptake of oxidized LDL (oxLDL) by macrophages. To define the structural and chemical criteria governing such cell recognition, we induced two modifications of lysines in LDL that mimic prototypic adducts present in oxLDL; namely, epsilon-amino charge-neutralizing pyrrolation by treatment with 2,5-hexanedione (hdLDL), and epsilon-amino charge-retaining pyridinium formation via treatment with 2,4,6-trimethylpyrylium (tmpLDL). Both modifications led to recognition by receptors on mouse peritoneal macrophages (MPM). To assess whether the murine scavenger receptor class A-I (mSR-A) was responsible for recognition of hdLDL or tmpLDL in MPM, we measured binding at 4 degrees C and degradation at 37 degrees C of these modified forms of (125)I-labeled LDL by mSR-A-transfected CHO cells. Although uptake and degradation of hdLDL by mSR-A-transfected CHO cells was quantitatively similar to that of the positive control, acLDL, tmpLDL was not recognized by these cells. However, both tmpLDL and hdLDL were recognized by 293 cells that had been transfected with CD36. In the human monocytic cell line THP-1 that had been activated with PMA, uptake of tmpLDL was significantly inhibited by blocking monoclonal antibodies to CD36, further suggesting recognition of tmpLDL by this receptor. Macrophage uptake and degradation of LDL oxidized by brief exposure to Cu(2+) was inhibited more effectively by excess tmpLDL and hdLDL than was more extensively oxidized LDL, consistent with the recognition of the former by CD36 and the latter primarily by SR-A.Collectively, these studies suggest that formation of specific pyrrole adducts on LDL leads to recognition by both the mSR-A and mouse homolog of CD36 expressed on MPM, while formation of specific pyridinium adducts on LDL leads to recognition by the mouse homolog of CD 36 but not by mSR-A. As such, these two modifications of LDL may represent useful models for dissecting the relative contributions of specific modifications on LDL produced during oxidation, to the cellular uptake of this heterogeneous ligand.

Animals↗
PubMed2002

Correlation between serum lipid profiles and the ratio and count of the CD16+ monocyte subset in peripheral blood of apparently healthy adults.

BACKGROUND AND PURPOSE: Deposited vascular oxidized low-density lipoproteins (LDLs) are important triggers of the transformation of circulatory monocytes into macrophages. CD16+ monocytes have been reported to be the precursors of tissue macrophages. In this study, we sought to determine the relationship between serum LDL-cholesterol and the percentage and count of the CD16+ monocyte subset in the peripheral blood of healthy adults. METHODS: We studied the correlations between serum lipid profiles and both peripheral CD16+ and CD36+ monocyte subset ratios and counts in apparently healthy adults (50 men and 50 women). Monocyte surface antigens CD16 and CD36 on CD14+ monocytes were detected using fluorescent triple staining and flow-cytometry. Surface staining was performed by incubating 1 x 10(6) blood mononuclear cells with phycocrythrin-conjugated anti-CD14, fluorescein isothiocyanate-conjugated anti-CD36, and respective control isotopes (mouse IgGs). A total of 5,000 cells were counted and the frequency of surface antigens was determined by FACscan. RESULTS: A significant positive link between LDL-cholesterol and the CD16+ subset ratio was found by linear correlation analysis (p < 0.05) but not by multivariate regression analysis. Both linear correlation analysis and ANOVA revealed a significant inverse link between high-density lipoprotein (HDL)-cholesterol and the CD16+ subset ratio (both p < 0.01). By multivariate regression analysis, gender was the main significant determinant for the CD16+ subset ratio. When serum total cholesterol (TC) was excluded from the analysis to avoid the interference from collinearity between serum TC and LDL (r = 0.84), HDL-cholesterol became independently and inversely linked to the CD16+ subset ratio. There were independent inverse links between HDL-cholesterol and the counts of all monocytes, CD16+ monocytes, and CD36+ monocytes. CONCLUSIONS: Our results suggest that circulating HDL-cholesterol may be much more important than LDL-cholesterol in affecting the transformation of circulatory monocytes into macrophages. The inverse link between HDL-cholesterol and the number of macrophage precursors in peripheral blood might contribute partly to the well-known antiatherogenic effect of HDL-cholesterol.

CD36 Antigens↗
PubMed2003

A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation.

Senile plaques found in the Alzheimer's disease brain are foci of local inflammatory reactions mediated by plaque-associated microglia. The interaction of microglia with compacted deposits of beta-amyloid (Abeta) fibrils results in the stimulation of intracellular Tyr kinase-based signaling cascades and cellular activation, leading to the secretion of proinflammatory molecules. This study identifies a cell surface receptor complex that mediates the binding of microglia to Abeta fibrils and the subsequent activation of intracellular signaling pathways leading to a proinflammatory response. The receptor complex includes the B-class scavenger receptor CD36, the integrin-associated protein/CD47, and the alpha(6)beta(1)-integrin. Antagonists of scavenger receptors, CD36, CD47, and alpha(6)beta(1) inhibited the adhesion of THP-1 monocytes to Abeta fibrils. In addition, peptide competitors of Abeta fibril interactions with CD36, scavenger receptors, CD47, and the alpha(6)beta(1)-integrin inhibited Abeta stimulation of Tyr kinase-based signaling cascades in both THP-1 monocytes and murine microglia as well as interleukin 1beta production. A scavenger receptor antagonist and antibodies specific for CD36 and the beta(1)-integrin subunit also inhibited the Abeta-stimulated generation of reactive oxygen species. Importantly, the principal components of this receptor complex are shared with those for other fibrillar proteins and thus represent general elements through which myeloid lineage cells recognize complex fibrillar proteins. Identification of the cell surface molecules that interact with Abeta fibrils and mediate their activation of intracellular signaling cascades represents a potential intervention point in the treatment of Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1994

[Genetic engineering in clinical pathology].

CD36 is a glycoprotein that is expressed on platelets, monocytes, and endothelial cells. To analyze the mechanism of CD36 deficiency on the platelet membrane, we have examined the expression of mRNA by RT-PCR and the Sau96I site on PCR products. In cases 3, 5, and 6, we have detected the normal size, but few products by agarose gel electrophoresis and in all cases, several restriction enzyme patterns with Sau96I digestion have been observed. These findings suggest that transcriptional control may affect the expression of the CD36 molecule on the platelet membrane and a different mechanism may be present for the transcription of the CD36 mRNA in megakaryocytes from monocytes.

Antigens, CD↗
PubMed2004

The role of alpha-tocopherol in preventing disease.

A role of oxidative stress in atherosclerosis lies on experimental results carried out in vitro and in animal models. In humans, the supplementation with the antioxidant vitamin E has given in some cases supportive results and in others no effects. From in vitro studies, a large amount of data has shown that alpha-tocopherol (the major component of vitamin E) regulates key events in the cellular pathogenesis of atherosclerosis. We first described the inhibition of protein kinase C (PKC) activity by alpha-tocopherol to be at the basis of the vascular smooth muscle cell growth inhibition by this compound. Subsequently, PKC was recognized to be the target of alpha-tocopherol in different cell types, including monocytes, macrophages, neutrophils, fibroblasts and mesangial cells. Inhibiting the activity of protein kinase C by alpha-tocopherol results in different events in different cell types: inhibition of platelet aggregation, of nitric oxide production in endothelial cells, of superoxide production in neutrophils and macrophages as well as impairment of smooth muscle cell proliferation. Adhesion molecule expression and inflammatory cell cytokine production are also influenced by alpha-tocopherol. Scavenger receptors, particularly important in the formation of atherosclerotic foam cells, are also modulated by alpha-tocopherol. The oxidized LDL scavenger receptors SR-A and CD36 are down regulated at the transcriptional level by alpha-tocopherol. The relevance of CD36 expression in the onset of atherosclerosis has been indicated by the protection against atherosclerosis by CD36 knockout mice. In conclusion, the effect of alpha-tocopherol against atherosclerosis is not due only to the prevention of LDL oxidation but also to the down regulation of the scavenger receptor CD36 and to the inhibition of PKC activity.

Animals↗