miR-155 in the Resolution of Atherosclerosis

Atherosclerosis is a chronic progressive inflammatory disease where advanced lesions can eventually completely obstruct blood flow resulting in clinical events, such as a myocardial infarction or stroke. Monocytes and macrophages are the dominant biologically active immune cells involved in atherosclerosis disease and play a pivotal role during initiation, progression, and regression of disease. Altering macrophage inflammation is critical to induce regression of atherosclerosis and microRNAs (miRs) have emerged as key regulators of the macrophage phenotype. MiRs are small noncoding RNAs that regulate gene expression. They are dysregulated during atherosclerosis development and are key regulators of macrophage function and polarization. MiRs are short nucleotide transcripts that are very stable in circulation and thus have potential as therapeutics and/or biomarkers in the context of atherosclerosis. Of relevance to this review is that inhibition of macrophage-specific miR-155 may be a viable therapeutic strategy to decrease inflammation associated with atherosclerosis. However, further studies on these miRs and advancements in miR therapeutic delivery are required for these therapeutics to advance to the clinical setting. Conjugated linoleic acid (CLA), a pro-resolving lipid mediator, is an agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. The biological activities of CLA have been documented to have anti-atherogenic effects in experimental models of atherosclerosis, inducing regression and impacting on monocyte and macrophage cells. Our work and that of others on PPAR-γ agonists and polyunsaturated fatty acids have shown that these mediators regulate candidate miRNAs and promote pro-resolving atherosclerotic plaque microenvironments

Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis

Background: Macrophages play a pivotal role in atherosclerotic plaque development. Recent evidence has suggested the glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, can attenuate pro-inflammatory responses in macrophages. We hypothesized that liraglutide could limit atherosclerosis progression in vivo via modulation of the inflammatory response. Methods: Human THP-1 macrophages and bone marrow-derived macrophages, from both wild-type C57BL/6 (WT) and apolipoprotein E null mice (ApoE−/−) were used to investigate the effect of liraglutide on the inflammatory response in vitro. In parallel, ApoE−/− mice were fed a high-fat (60% calories from fat) high-cholesterol (1%) diet for 8 weeks to induce atherosclerotic disease progression with/without daily 300 μg/kg liraglutide administration for the final 6 weeks. Macrophages were analysed for MΦ1 and MΦ2 macrophage markers by Western blotting, RT-qPCR, ELISA and flow cytometry. Atherosclerotic lesions in aortae from ApoE−/− mice were analysed by en face staining and monocyte and macrophage populations from bone marrow derived cells analysed by flow cytometry. Results: Liraglutide decreased atherosclerotic lesion formation in ApoE−/− mice coincident with a reduction in pro-inflammatory and increased anti-inflammatory monocyte/macrophage populations in vivo. Liraglutide decreased IL-1beta in MΦ0 THP-1 macrophages and bone marrow-derived macrophages from WT mice and induced a significant increase in the MΦ2 surface marker mannose receptor in both MΦ0 and MΦ2 macrophages. Significant reduction in total lesion development was found with once daily 300 μg/kg liraglutide treatment in ApoE−/− mice. Interestingly, liraglutide inhibited disease progression at the iliac bifurcation suggesting that it retards the initiation and development of disease. These results corresponded to attenuated MΦ1 markers (CCR7, IL-6 and TNF-alpha), augmented MΦ2 cell markers (Arg-1, IL-10 and CD163) and finally decreased MΦ1-like monocytes and macrophages from bone marrow-derived cells. Conclusions: This data supports a therapeutic role for liraglutide as an atheroprotective agent via modulating macrophage cell fate towards MΦ2 pro-resolving macrophages.Science Foundation IrelandEuropean Foundation for the Study of Diabete

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Additional file 9: Figure S8. Glucose measurements from ApoE-/- mice. ApoE-/- mice were fed a LFD or HFHCD for 2 weeks. From weeks 2-8 mice continued on the diets while also receiving daily subcutaneous injections of 300μg/kg liraglutide or PBS. Mice underwent glucose testing every 2 weeks via a tail-vein pin prick procedure. a| represents glucose levels during the liraglutide dosing period (week 2) and b| the glucose levels of mice for the whole study weeks 2-8. Error bars are representative of 16 mice per group (n=16). Statistical analysis was carried out performing a Kruskal–Wallis test followed by Dunn’s multiple comparison post-test. Statistical significance was considered when **p<0.01 while p>0.05 was considered NS. Stars above the boxes represent comparisons against the LFD group

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Additional file 1. Additional methods and tables

Novel thioglycoside analogs of ?-galactosylceramide stimulate cytotoxicity and preferential Th1 cytokine production by human invariant natural killer T cells

Invariant natural killer T (iNKT) cells recognize glycolipid antigens bound to CD1d molecules on antigen-presenting cells. Therapeutic activation of iNKT cells with the xenogeneic glycolipid ?-galactosylceramide (?-GalCer) can prevent and reverse tumor growth in murine models, but clinical trials using ?-GalCer-stimulated human iNKT cells have shown limited efficacy. We synthesized a series of thioglycoside analogs of ?-GalCer with different substituents to the galactose residue and found that two of these compounds, XZ7 and XZ11, bound to CD1d-transfected HeLa cells and activated lines of expanded human iNKT cells. Both compounds stimulated cytolytic degranulation by iNKT cells and while XZ7 preferentially stimulated the production of the antitumor cytokine interferon-? (IFN-?), XZ11 preferentially stimulated interleukin-4 (IL-4) production. This biased T helper type 1 effector profile of XZ7 was also evident when iNKT were stimulated with dendritic cells presenting this glycolipid. Separate analysis of the responses of CD4+, CD8?+ and CD4?CD8? iNKT cells indicated that XZ7 preferentially activated CD8?+ iNKT cells, and to a lesser degree, CD4?CD8? iNKT cells. The partial agonist effect of glycolipid XZ7, inducing cytotoxicity and IFN-? production but not IL-4 production, indicates that specific protumour activities of iNKT cells can be abolished, while preserving their antitumor activities, by introducing structural modifications to ?-GalCer. Since XZ7 was much less potent than ?-GalCer as an iNKT cell agonist, it is unlikely to be superior to ?-GalCer as a therapeutic agent for cancer, but may serve as a parent compound for developing more potent structural analogs

Pharyngeal Co-Infections with Monkeypox Virus and Group A Streptococcus, United States, 2022

We report 2 cases of pharyngeal monkeypox virus and group A Streptococcus co-infection in the United States. No rash was observed when pharyngitis symptoms began. One patient required intubation before mpox was diagnosed. Healthcare providers should be aware of oropharyngeal mpox manifestations and possible co-infections; early treatment might prevent serious complications