The aorta can act as a site of naïve CD4+ T-cell priming

Aims: Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T-cell activation in the arterial wall remain poorly understood. Methods and results: Here, we have identified naïve T cells in the aorta of wild-Type and T-cell receptor transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with both kinetics and frequency of T-cell activation found to be similar to splenic and lymphoid T cells. Aortic homing of naïve T cells is regulated at least in part by the P-selectin glycosylated ligand-1 receptor. In experimental atherosclerosis the aorta supports CD4+ T-cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion. Conclusion: Our results demonstrate that the aorta can support T-cell priming and that naïve T cells traffic between the circulation and vessel wall. These data underpin the paradigm that local priming of T cells specific for plaque antigens contributes to atherosclerosis progression

D025 Phagocytosis is pivotal in the beneficial effect of bone marrow mononuclear cellsbased therapy for myocardial infarction

Cell-based therapy is a promising option for treatment of cardiovascular diseases. Based on experimental studies demonstrating that bone marrow-derived mononuclear cells (BMMNCs) improve the functional recovery after ischemia, clinical trials were initiated to address this new therapeutic concept. BMMNCs improve neovascularization of ischemic tissue by a broad repertoire of potential therapeutic actions. Whereas initial studies documented that the cells incorporate and differentiate to cardiovascular cells, other studies suggested that short-time paracrine mechanisms mediate the beneficial effects. Here, we hypothesized that BMMNCs have a phagocytic ability, and switch to a proangiogenic phenotype after engulfment of apoptotic cells. Activation of such angiogenic program may be pivotal in the beneficial effect of BMMNCs-based therapy. In vitro, wildtype (WT) BMMNCs ingestion of apoptotic cells upregulated the release of proangiogenic factors VEGF and HGF by 15- and 5-fold, respectively. In contrast, BMMNCs collected from mice deficient in MFG-E8, a protein that is required for attachment and engulfment of apoptotic cells by phagocytes, displayed lower phagocytic ability, leading to decrease in VEGF and HGF release. The capacity of BMMNCs to differentiate into cells with endothelial phenotype was similar in control and MFG-E8-deficient cells. In an in vivo model of mice myocardial infaction (MI), transplantation of WT BMMNCs increased fractionnal shortening (120 % of untreated control, p<0.05), 14 days after MI. Size of the infarct scar was reduced by 30 % (p<0.05 vs untreated control), and capillary density in the infarct border zone was raised by 10 % (p<0.05 vs untreated control) in the WT BMMNCs group. In contrast, transplantation of MFG-E8 deficient BMMNCs displayed no significant effect on cardiac function, infarct size or angiogenesis in the ischemic myocardium. Four days after MI, VEGF protein levels were raised by 1.4 fold in the myocardium of WT BMMNCs treated animals compared to untreated controls (p<0.05), while treatment with MFG-E8 deficient BMMNCs failed to raise VEGF levels. Taken together, these results suggest that phagocytosis of apoptotic cells reprograms BMMNCs into a proangiogenic phenotype. Hence, the therapeutic effect of transplanted BMMNCs depends, at least in part, on their phagocytic ability

D022 Natural CD4/CD25/Foxp3 regulatory t cells modulate post-ischemic inflammatory response: role in neovascularization

CD4+ and CD8+ T lymphocytes control revascularization after vascular occlusion. T cell activation is mediated by two major costimulatory signalings: the B7/CD28 and the CD40-CD40 ligand pathways. Interestingly, CD28 interactions with the structurally related ligands B7-1 and B7-2 are also required for the generation and homeostasis of CD4+CD25+ regulatory T cells (Treg), whichactively maintain immunological tolerance to self and nonself antigens. We hypothesized that naturally arising Treg modulate the immuno-inflammatory response to ischemic injury, and subsequently vessel growth.Ischemia was induced by right femoral artery ligation in CD28-deficient mice (n=10 per group). After 21 days of ischemia, CD28 deficiency showed a profound reduction in Treg number and upregulated post-ischemic inflammatory response and neovascularization. Similarly, injection of splenocytes isolated from CD28-/- mice in Rag1-/- mice with hindlimb ischemia increased angiographic score, foot perfusion, and capillary density by 2.2-, 2.3- and 1.1-fold, respectively, compared to PBS-injected Rag1-/- mice. These effects were associated with enhanced accumulation of CD3-positive T cells and Mac-3 positive macrophages in the ischemic leg of Rag1-/- mice treated with CD28-/- splenocytes. Interestingly, cotransfer of Treg with CD28-/- splenocytes in Rag1- /- mice abrogated activation of neovascularization induced by CD28-/- splenocytes. Inflammatory cells accumulation was also decreased in Rag1-/- transplanted with both Treg and CD28-/- splenocytes compared to mice receiving CD28-/- splenocytes only. In contrast, treatment of C57Bl/6 Wild-Type mice with an anti- CD25 antibody (PC61) markedly reduced endogenous Treg levels in blood and spleen. At day 14 of ischemia, inflammatory response and neovascularization were markedly increased in anti-CD25 treated Wild-Type mice compared to untreated mice. These results provide new insights into the immunoregulation of post-ischemic neovascularization

Extracellular matrix protein-1 as a mediator of inflammation-induced fibrosis after myocardial infarction

Irreversible fibrosis is a hallmark of myocardial infarction (MI) and heart failure. Extracellular matrix protein-1 (ECM-1) is up-regulated in these hearts, localized to fibrotic, inflammatory, and perivascular areas. ECM-1 originates predominantly from fibroblasts, macrophages, and pericytes/vascular cells in uninjured human and mouse hearts, and from M1 and M2 macrophages and myofibroblasts after MI. ECM-1 stimulates fibroblast-to-myofibroblast transition, up-regulates key fibrotic and inflammatory pathways, and inhibits cardiac fibroblast migration. ECM-1 binds HuCFb cell surface receptor LRP1, and LRP1 inhibition blocks ECM-1 from stimulating fibroblast-to-myofibroblast transition, confirming a novel ECM-1-LRP1 fibrotic signaling axis. ECM-1 may represent a novel mechanism facilitating inflammation-fibrosis crosstalk

Spread of psoriasiform inflammation to remote tissues is restricted by the atypical chemokine receptor ACKR2

Elucidating the poorly defined mechanisms by which inflammatory lesions are spatially restricted in vivo, is of critical importance in understanding skin disease. Chemokines are the principal regulators of leukocyte migration and are essential in the initiation and maintenance of inflammation. The membrane-bound psoriasis associated atypical chemokine receptor ACKR2 binds, internalises and degrades most pro-inflammatory CC-chemokines. Here we investigate the role of ACKR2 in limiting the spread of cutaneous psoriasiform inflammation to sites that are remote from the primary lesion.  Circulating factors capable of regulating ACKR2 function at remote sites were identified and examined using a combination of clinical samples, relevant primary human cell cultures, in vitro migration assays and the imiquimod-induced model of psoriasiform skin inflammation. Localised inflammation and IFN together upregulate ACKR2 in remote tissues, protecting them from the spread of inflammation. ACKR2 controls inflammatory T-cell chemotaxis and positioning within the skin, preventing an epidermal influx that is associated with lesion development. Our results have important implications for our understanding of how spatial restriction is imposed on the spread of inflammatory lesions, and highlight systemic ACKR2 induction as a therapeutic strategy in the treatment and prevention of psoriasis and potentially a broad range of other immune-mediated diseases

Modelling the sulfate capacity of simulated radioactive waste borosilicate glasses

The capacity of simulated high-level radioactive waste borosilicate glasses to incorporate sulfate has been studied as a function of glass composition. Combined Raman, 57Fe Mössbauer and literature evidence supports the attribution of coordination numbers and oxidation states of constituent cations for the purposes of modelling, and results confirm the validity of correlating sulfate incorporation in multicomponent borosilicate radioactive waste glasses with different models. A strong compositional dependency is observed and this can be described by an inverse linear relationship between incorporated sulfate (mol% SO42−) and total cation field strength index of the glass, Σ(z/a2), with a high goodness-of-fit (R2 ≈ 0.950). Similar relationships are also obtained if theoretical optical basicity, Λth (R2 ≈ 0.930) or non-bridging oxygen per tetrahedron ratio, NBO/T (R2 ≈ 0.919), are used. Results support the application of these models, and in particular Σ(z/a2), as predictive tools to aid the development of new glass compositions with enhanced sulfate capacities

From basic mechanisms to clinical applications in heart protection, new players in cardiovascular diseases and cardiac theranostics: meeting report from the third international symposium on "New frontiers in cardiovascular research"

In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients' cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia-reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients' outcome

Cardiomyocyte and vascular smooth muscle independent 11β-hydroxysteroid dehydrogenase 1 amplifies infarct expansion, hypertrophy and the development of heart failure following myocardial infarction in male mice

Global deficiency of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that regenerates glucocorticoids within cells, promotes angiogenesis, and reduces acute infarct expansion after myocardial infarction (MI), suggesting that 11β-HSD1 activity has an adverse influence on wound healing in the heart after MI. The present study investigated whether 11β-HSD1 deficiency could prevent the development of heart failure after MI and examined whether 11β-HSD1 deficiency in cardiomyocytes and vascular smooth muscle cells confers this protection. Male mice with global deficiency in 11β-HSD1, or with Hsd11b1 disruption in cardiac and vascular smooth muscle (via SM22α-Cre recombinase), underwent coronary artery ligation for induction of MI. Acute injury was equivalent in all groups. However, by 8 weeks after induction of MI, relative to C57Bl/6 wild type, globally 11β-HSD1-deficient mice had reduced infarct size (34.7 ± 2.1% left ventricle [LV] vs 44.0 ± 3.3% LV, P = .02), improved function (ejection fraction, 33.5 ± 2.5% vs 24.7 ± 2.5%, P = .03) and reduced ventricular dilation (LV end-diastolic volume, 0.17 ± 0.01 vs 0.21 ± 0.01 mL, P = .01). This was accompanied by a reduction in hypertrophy, pulmonary edema, and in the expression of genes encoding atrial natriuretic peptide and β-myosin heavy chain. None of these outcomes, nor promotion of periinfarct angiogenesis during infarct repair, were recapitulated when 11β-HSD1 deficiency was restricted to cardiac and vascular smooth muscle. 11β-HSD1 expressed in cells other than cardiomyocytes or vascular smooth muscle limits angiogenesis and promotes infarct expansion with adverse ventricular remodeling after MI. Early pharmacological inhibition of 11β-HSD1 may offer a new therapeutic approach to prevent heart failure associated with ischemic heart disease

B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction.

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C(hi) monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.This work was supported by Inserm, British Heart Foundation (Z.M.), European Research Council (Z.M.), Fondation Coeur et Recherche (Z.M., T.S., N.D.), Fondation pour la Recherche Medicale (J.S.S.), European Union Seven Framework programme TOLERAGE (Z.M.), Fondation Leducq transatlantic network (C.J.B., D.T., A.T., J.S.S., Z.M.), National Institutes of Health grants AI56363 and AI057157, and a grant from The Lymphoma Research Foundation (T.F.T).This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nm.3284