Thematic review series: The Immune System and Atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis

Tobias, Peter S.; Curtiss, Linda K.

doi:10.1194/jlr.r400015-jlr200

Cited by 100 publications

(66 citation statements)

References 92 publications

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“…20). Interestingly, LXR activation has been shown to decrease the responsiveness of genes that are targets of NF-B (41), consistent with the inverse association in the present data between the mRNAs for LXR␣ and either VCAM-1 or MCP-1 (Fig.…”

Section: Discussionsupporting

confidence: 81%

“…In the WT recipient, plaques become rapidly exposed to a plasma environment containing a relative increase in HDL and decrease in non-HDL cholesterol, changes which are expected to promote cholesterol efflux from foam cells and thereby reverse inflammatory changes associated with the lipid loading of macrophages (e.g., refs. [18][19][20]. Thus, CD68 ϩ cells were selected from the plaques of pretransplant and recipient mice, and the expression of genes related to cholesterol efflux (PPAR␥, LXR␣, ABCA1, and SR-BI) and inflammation (VCAM, MCP-1) was measured (Fig.…”

Section: Effects Of the Correction Of Dyslipidemia On Cholesterol Effmentioning

confidence: 99%

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Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

Trogan

Feig

Doğan

et al. 2006

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

311

360

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Atherosclerosis regression is an important clinical goal. In previous studies of regression in mice, the rapid loss of plaque foam cells was explained by emigration to lymph nodes, a process reminiscent of dendritic cells. In the present study, plaque-containing arterial segments from apoE ؊/؊ mice were transplanted into WT recipient normolipidemic mice or apoE ؊/؊ mice. Three days after transplant, in the WT regression environment, plaque size decreased by Ϸ40%, and foam cell content by Ϸ75%. In contrast, both parameters increased in apoE ؊/؊ recipients. Foam cells were isolated by laser capture microdissection. In WT recipients, there were 3-to 6-fold increases in foam cells of mRNA for liver X receptor ␣ and cholesterol efflux factors ABCA1 and SR-BI. Although liver X receptor ␣ was induced, there was no detectable expression of its putative activator, peroxisome proliferator-activated receptor ␥. Expression levels of VCAM or MCP-1 were reduced to 25% of levels in pretransplant or apoE ؊/؊ recipient samples, but there was induction at the mRNA and protein levels of chemokine receptor CCR7, an essential factor for dendritic cell migration. Remarkably, when CCR7 function was abrogated in vivo by treatment of WT recipients with antibodies to CCR7 ligands CCL19 and CCL21, lesion size and foam cell content were substantially preserved. In summary, in foam cells during atherosclerosis regression, there is induction of CCR7 and a requirement for its function. Taken with the other gene expression data, these results in vivo point to complex relationships among the immune system, nuclear hormone receptors, and inflammation during regression.cholesterol efflux ͉ dendritic cell ͉ macrophage ͉ monocyte ͉ nuclear hormone receptor M ouse models of atherosclerosis regression are relatively few.However, similarities between atherosclerosis in humans and in mice deficient in apolipoprotein E (apoE Ϫ/Ϫ ) or the LDL receptor (e.g., see ref. 1) suggest that molecular mechanisms underlying regression in mouse models could be relevant to the reduction of the large plaque burden in the middle-aged and older human population.We have previously described a mouse model of regression. First, plaques were allowed to develop in apoE Ϫ/Ϫ mice, then a segment of either thoracic aortic (2) or aortic arch (3, 4) was transplanted into the abdominal aorta of a WT recipient, quickly changing the plasma lipid environment from hyper to normolipidemia. As a control, an aortic segment was transplanted into an apoE Ϫ/Ϫ mouse. By 1 month, in the regression environment (WT recipient), essentially all of the foam cells disappeared from plaques (4), with many no longer visible after 3 days (5). In contrast, in the progression environment (apoE Ϫ/Ϫ recipient), plaque size and foam cell content increased over time.In a recent study, we showed that the rapid depletion of foam cells in the regression environment was correlated with a substantial number of these cells emigrating to lymph nodes (5). Interestingly, the emigrating cells expressed markers of den...

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Section: Discussionsupporting

confidence: 81%

Section: Effects Of the Correction Of Dyslipidemia On Cholesterol Effmentioning

confidence: 99%

Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

Trogan

Feig

Doğan

et al. 2006

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

311

360

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“…Cellular receptor for LPS TLR4 plays an important role in infection as well as in chronic diseases, such as rheumatoid arthritis (26), atherosclerosis (27,28), and inflammation caused by tissue damage (e.g. by ischemia-reperfusion (29) or in hemorrhage-induced acute lung injury (30)).…”

Section: Discussionmentioning

confidence: 99%

Free Thiol Group of MD-2 as the Target for Inhibition of the Lipopolysaccharide-induced Cell Activation

Manček-Keber

Gradišar

Pestaña

et al. 2009

Journal of Biological Chemistry

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MD-2 is a part of the Toll-like 4 signaling complex with an indispensable role in activation of the lipopolysaccharide (LPS) signaling pathway and thus a suitable target for the therapeutic inhibition of TLR4 signaling. Elucidation of MD-2 structure provides a foundation for rational design of inhibitors that bind to MD-2 and inhibit LPS signaling. Since the hydrophobic binding pocket of MD-2 provides little specificity for inhibitors, we have investigated targeting the solvent-accessible cysteine residue within the hydrophobic binding pocket of MD-2. Compounds with affinity for the hydrophobic pocket that contain a thiol-reactive group, which mediates covalent bond formation with the free cysteine residue of MD-2, were tested. Fluorescent compounds 2-(4-(iodoacetamido)anilino)naphthalene-6-sulfonic acid and N-pyrene maleimide formed a covalent bond with MD-2 through Cys 133 and inhibited LPS signaling. Cell activation was also inhibited by thiol-reactive compounds JTT-705 originally targeted against cholesterol ester transfer protein and antirheumatic compound auranofin. Oral intake of JTT-705 significantly inhibited endotoxin-triggered tumor necrosis factor ␣ production in mice. The thiol group of MD-2 also represents the target of environmental or endogenous thiol-reactive compounds that are produced in inflammation. TLR4 is a receptor for lipopolysaccharide (LPS)4 a major constituent of outer membrane of Gram-negative bacteria. MD-2 is the final LPS-binding protein in the recognition cascade before TLR4 transmits the signal across the cell membrane to activate the inflammatory response. MD-2 binds to the ectodomain of TLR4 and binds LPS either alone or in complex with TLR4 (1, 2). Mice deficient in MD-2 survive endotoxic shock (3). MD-2 has been indispensable in almost all investigated conditions of TLR4-triggered inflammation; therefore, it could represent the "Achilles' heel" of the inflammatory response to LPS and a target for a pharmacological intervention in endotoxemia as well as other conditions involving cell activation mediated by TLR4 (4, 5). The existence of a single free cysteine residue among the seven cysteine residues has been predicted from MD-2 mutagenesis (6, 7) and molecular modeling proposed that Cys 133 lies in the hydrophobic pocket (8, 9). The hydrophobic binding site of MD-2 was also mapped by an apolar probe, bis-ANS, which does not contain acyl chains as most LPS antagonists yet preserves the characteristic structural motif of lipid A, consisting of a hydrophobic region and a pair of separated negatively charged groups (10). Crystal structures of MD-2 with bound eritoran or lipid IVa confirmed the location of Cys 133 in the hydrophobic pocket in close vicinity of bound lipid A derivatives (11, 12). The free cysteine residue inside the binding pocket can thus be a target for irreversible inhibition of MD-2 activity. An inhibitory mechanism based on a covalent modification of a free cysteine residue in the active or binding site of a protein has been demonstrated for other proteins, s...

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“…Moreover, ADRP augments TNFα, MCP-1, and IL-6 induction in acLDL-induced macrophages, suggesting that enhancing inflammation might be one role of ADRP in atherosclerosis . In addition, LPS and other Toll-like receptor (TLR) ligands, which have been previously shown to increase macrophage TG and CE accumulation (Tobias and Curtiss, 2005;Posokhova et al, 2008), increase the expression of ADRP as part of a coordinated change in macrophage physiology (Feingold et al, 2010).…”

Section: Adrpmentioning

confidence: 99%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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Thematic review series: The Immune System and Atherogenesis. Paying the price for pathogen protection: toll receptors in atherogenesis

Cited by 100 publications

References 92 publications

Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

Free Thiol Group of MD-2 as the Target for Inhibition of the Lipopolysaccharide-induced Cell Activation

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

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