Hypoxia increases membranal and secreted HLA-DR in endothelial cells, rendering them T-cell activators

Lahat, Nitza; Bitterman, Haim; Weiss-Cerem, Lea; Rahat, Michal A.

doi:10.1111/j.1432-2277.2011.01304.x

Cited by 6 publications

(6 citation statements)

References 47 publications

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“…50 The human homologs to mouse H2-Aa, H2-Ab1 , and H2-Ea , HLA-DR and HLA-DQ , are major histocompatibility complex class II members that regulate T-cell–dependent immune responses. Vascular SMCs in atherosclerotic lesions express HLA-DR , 51 and as studies have shown that hypoxia induces both HLA-DR expression and secretion in EC cultures, 52 it is likely that MAEC expresses this transcript as part of the inflammatory response in atherogenesis as we have seen here. Although the HLA-DQ transcripts are also expressed in ECs, 53 little is known about the HLA-DQ subtypes in the context of atherosclerosis and why they would be downregulated in atherosusceptible conditions as we show here.…”

Section: Discussionsupporting

confidence: 71%

Gene Expression Analyses of Mouse Aortic Endothelium in Response to Atherogenic Stimuli

Erbilgin

Siemers

Kayne

et al. 2013

ATVB

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Objective Endothelial cells are central to the initiation of atherosclerosis, yet there has been limited success in studying their gene expression in the mouse aorta. To address this, we developed a method for determining the global transcriptional changes that occur in the mouse endothelium in response to atherogenic conditions and applied it to investigate inflammatory stimuli. Approach and Results We characterized a method for the isolation of endothelial cell RNA with high purity directly from mouse aortas and adapted this method to allow for the treatment of aortas ex vivo before RNA collection. Expression array analysis was performed on endothelial cell RNA isolated from control and hyperlipidemic prelesion mouse aortas, and 797 differentially expressed genes were identified. We also examined the effect of additional atherogenic conditions on endothelial gene expression, including ex vivo treatment with inflammatory stimuli, acute hyperlipidemia, and age. Of the 14 most highly differentially expressed genes in endothelium from prelesion aortas, 8 were also perturbed significantly by ≥1 atherogenic conditions: 2610019E17Rik, Abca1, H2-Ab1, H2-D1, Pf4, Ppbp, Pvrl2, and Tnnt2. Conclusions We demonstrated that RNA can be isolated from mouse aortic endothelial cells after in vivo and ex vivo treatments of the murine vessel wall. We applied these methods to identify a group of genes, many of which have not been described previously as having a direct role in atherosclerosis, that were highly regulated by atherogenic stimuli and may play a role in early atherogenesis.

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Section: Discussionsupporting

confidence: 71%

Gene Expression Analyses of Mouse Aortic Endothelium in Response to Atherogenic Stimuli

Erbilgin

Siemers

Kayne

et al. 2013

ATVB

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“…It is possible that the changes in macrophage volume and shape observed in early AMD may represent an early phenotypic response to choroidal hypoxia. Another suggestion of hypoxia in early and late AMD choroid is expression of HLA-DR by choriocapillaris endothelial cells (results not shown), which, as demonstrated by Lahat et al, 40 occurred in hypoxic endothelial cells in vitro.…”

Section: Discussionmentioning

confidence: 57%

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration

McLeod

Bhutto

Edwards

et al. 2016

Invest. Ophthalmol. Vis. Sci.

116

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PurposeIncreasing evidence suggests a role for macrophages in the pathogenesis of age-related macular degeneration (AMD). This study examined choroidal macrophages and their activation in postmortem eyes from subjects with and without AMD.MethodsChoroids were incubated with anti-ionized calcium-binding adapter molecule 1 (anti-IBA1) to label macrophages, anti-human leukocyte antigen-antigen D-related (anti-HLA-DR) as a macrophage activation marker, and Ulex europaeus agglutinin lectin to label blood vessels. Whole mounts were imaged using confocal microscopy. IBA1- and HLA-DR–positive (activated) cells were counted in submacula, paramacula, and nonmacula, and cell volume and sphericity were determined using computer-assisted image analysis.ResultsIn aged control eyes, the mean number of submacular IBA1+ and HLA-DR+ macrophages was 433/mm2 and 152/mm2, respectively. In early AMD eyes, there was a significant increase in IBA1+ and HLA-DR+ cells in submacula compared to those in controls (P = 0.0015 and P = 0.008, respectively). In eyes with neovascular AMD, there were significantly more HLA-DR+ cells associated with submacular choroidal neovascularization (P = 0.001). Mean cell volume was significantly lower (P ≤ 0.02), and sphericity was significantly higher (P ≤ 0.005) in all AMD groups compared to controls.ConclusionsThe average number of IBA1+ macrophages in submacular and paramacular choroid was significantly higher in early/intermediate AMD compared to that in aged controls. HLA-DR+ submacular macrophages were significantly increased in all stages of AMD, and they were significantly more round and smaller in size in the submacular AMD choroid, suggesting their activation. These findings support the concept that AMD is an inflammatory disease.

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“…Next, we evaluated the presence of EMMPRIN protein in exosomes, by precipitating the exosomes using ultracentrifugation, an accepted method for exosome isolation (Lahat et al, 2011). However, EMMPRIN was exclusively found in the supernatants and was not sedimented at all after ultracentrifugation, indicating that it is not found in exosomes (Figure 3C).…”

Section: Resultsmentioning

confidence: 99%

Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN

Amit-Cohen¹,

Rahat²,

Rahat³

2013

Front. Physiol.

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Tumor macrophages are generally considered to be alternatively/M2 activated to induce secretion of pro-angiogenic factors such as VEGF and MMPs. EMMPRIN (CD147, basigin) is overexpressed in many tumor types, and has been shown to induce fibroblasts and endothelial cell expression of MMPs and VEGF. We first show that tumor cell interactions with macrophages resulted in increased expression of EMMPRIN and induction of MMP-9 and VEGF. Human A498 renal carcinoma or MCF-7 breast carcinoma cell lines were co-cultured with the U937 monocytic-like cell line in the presence of TNFα (1 ng/ml). Membranal EMMPRIN expression was increased in the co-cultures (by 3–4-folds, p < 0.01), as was the secretion of MMP-9 and VEGF (by 2–5-folds for both MMP-9 and VEGF, p < 0.01), relative to the single cultures with TNFα. Investigating the regulatory mechanisms, we show that EMMPRIN was post-translationally regulated by miR-146a, as no change was observed in the tumoral expression of EMMPRIN mRNA during co-culture, expression of miR-146a was increased and its neutralization by its antagomir inhibited EMMPRIN expression. The secretion of EMMPRIN was also enhanced (by 2–3-folds, p < 0.05, only in the A498 co-culture) via shedding off of the membranal protein by a serine protease that is yet to be identified, as demonstrated by the use of wide range protease inhibitors. Finally, soluble EMMPRIN enhanced monocytic secretion of MMP-9 and VEGF, as inhibition of its expression levels by neutralizing anti-EMMPRIN or siRNA in the tumor cells lead to subsequent decreased induction of these two pro-angiogenic proteins. These results reveal a mechanism whereby tumor cell-macrophage interactions promote angiogenesis via an EMMPRIN-mediated pathway.

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Hypoxia increases membranal and secreted HLA-DR in endothelial cells, rendering them T-cell activators

Cited by 6 publications

References 47 publications

Gene Expression Analyses of Mouse Aortic Endothelium in Response to Atherogenic Stimuli

Gene Expression Analyses of Mouse Aortic Endothelium in Response to Atherogenic Stimuli

Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration

Tumor cell-macrophage interactions increase angiogenesis through secretion of EMMPRIN

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