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Cardiac Lymphatics Mediate the Resolution of Inflammation Unravelling the Atheroprotective Mechanisms of LDL Imm Unization

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Cardiac Lymphatics Mediate the Resolution of Inflammation Unravelling the Atheroprotective Mechanisms of LDL Imm Unization RESEARCH HIGHLIGHTS d ATHEROSCLEROSIS ite cholesterol levels. LDL im L re u autoimmunity t a N was also r e Unravelling the atheroprotective g associated with n i r p S / increased y mechanisms of LDL imm unization b s er cholesterol m m A study provides new insights To assess the immune responses of . Su excretion in : V it d faeces, reduced into the mechanisms of immune LDL- reactive T cells and the effect e r responses against LDL, showing that on atherosclerosis, the investigators C vascular inflammation, anti- LDL immunoreactivity induces used hypercholesterolaemic mice and atheroprotection. antibody- mediated clearance expressing human apoB100, adoptive “We show that targeting of LDL from blood, increases cell transfer assays, and generated LDL- reactive T cells can enhance cholesterol excretion, and reduces transgenic mice in which the atheroprotective immunity and vascular inflammation. “We have majority of CD4+ T cells had T-cell that vaccination against LDL addressed the paradox of athero- receptors that recognized human components may be an attractive immunity,” remarks lead investigator apoB100. The experiments showed way to prevent atherosclerosis,” Göran Hansson. “The local immune that a subpopulation of LDL-reactive concludes Hansson. The research response of the atherosclerotic T cells survived clonal selection of team is now assessing different plaque is largely directed against self- reactivity in the thymus and apoB100 epitopes and various LDL, is pro-inflammatory, and could be activated later in life. immunization routes and adjuvants involves mediators known to be After activation by antigen vaccination for vaccination to optimize pro- atherosclerotic (CD4+ T helper 1 recognition in lymphoid organs, atheroprotective immune responses. cells and cytokines such as IFNγ), a substantial proportion of these against LDL Irene Fernández-Ruiz and yet immunization with LDL LDL- reactive T cells developed components elicits a protective immune response into T follicular helper cells that ORIGINAL ArtiCLE Gisterå, A. et al. LDL-reactive may be an T cells regulate plasma cholesterol levels and that reduces atherosclerosis,” evoked a strong B-cell response, attractive way development of atherosclerosis in humanized he explains. with production of antibodies against hypercholesterolemic mice. Circulation https://doi. to prevent org/10.1161/CIRCULATIONAHA.118.034076 (2018) The research team had previously LDL. These anti-LDL antibodies FUrthER READING Ruparelia, N. et al. + shown that CD4 T cells recognize induced LDL clearance from the atherosclerosis Inflammatory processes in cardiovascular disease: oligopeptides of the LDL component circulation through immune- a route to targeted therapies. Nat. Rev. Cardiol. 14, 133–144 (2017) apolipoprotein B100 (apoB100). complex formation, lowering plasma ACUTE CORONARY SYNDROMES Cardiac lymphatics mediate the resolution of inflammation Cardiac lymphatics expand in mouse mice, but unchanged at earlier time hearts after myocardial infarction (MI); points, when lymphatic sprouting treatment with vascular endothelial had not yet occurred, suggesting that growth factor C (VEGF-C) increases the expansion lymphangiogenesis accelerates the this lymphangiogenic response, which of lymphatic resolution of inflammation after MI. improves cardiac function. According to vessels after The constitutive deletion of lymphatic a new study, the expansion of lymphatic vessel endothelial hyaluronic acid vessels after MI promotes heart repair MI promotes receptor 1 (LYVE1) did not affect cardiac by increasing immune cell clearance. heart repair lymphangiogenesis at day 7 after MI, but A previous study suggested that by increasing Lyve1─/─ mice had an increased number VEGF- C-induced lymphangiogenesis of leukocytes in the heart compared with improves cardiac outcome after MI by immune cell wild- type mice, whereas the number was Limited Summersby/Springer Nature V. Credit: restoring interstitial fluid equilibrium. clearance reduced in mediastinal lymph nodes. the context of cardiovascular injury Paul Riley and colleagues hypothesized At day 21 after MI, Lyve1─/─ mice showed as an essential parallel strategy to that lymphatic vessels in the heart might reduced cardiac function and increased cell- based repair or regeneration,” also influence the immune response scarring compared with wild-type mice. explains Riley, adding that future studies after injury, a phenomenon already Together, these results indicate that include the screening of small-molecule described in peripheral tissues during the clearance of immune cells by the inducers of lymphangiogenesis and wound healing. “This is an entirely lymphatics is dependent on LYVE1 and immune cell clearance as the first stage novel finding that was not previously regulates cardiac outcome after MI. of a drug-discovery pipeline. appreciated in the context of heart “This study highlights the cardiac Alexandra Le Bras injury,” says Riley. In mice treated with lymphatics as a potential therapeutic ORIGINAL ArtiCLE Vieira, J. M. et al. The cardiac VEGF- C, the number of immune cells target in ischaemic heart disease, but also lymphatic system stimulates resolution of in cardiac tissue was reduced 7 days demonstrates the need to condition the inflammation following myocardial infarction. J. Clin. Invest. https://doi.org/10.1172/JCI97192 (2018) after MI compared with vehicle-treated local inflammatory environment in NATURE REVIEWS | CARDIOLOGY VOLUME 15 | OCTOBER 2018 | 583.
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