The aorta can act as a site of naıve CD41 T-cell priming

Aims - Aortic adaptive immunity plays a crucial 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 TCR transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with a similar activation profile 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 (PSGL-1) receptor. In experimental atherosclerosis the aorta supports CD4+ T cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion. Conclusions - 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

Iodine speciation in basaltic melts at depth

The speciation of iodine in basalts has been investigated by combining in situ X-ray diffraction at high pressures and temperatures up to 4.9 GPa and 1600 °C, and Raman spectroscopy on recovered high pressure glasses at ambient conditions. Both methods point to iodine being oxidized in basalts, whether molten or quenched as glasses. Observed interatomic distances and Raman vibrational modes are consistent with iodine being dissolved as complex iodate groups alike polyiodates or periodates, not as $\mathrm{IO}_3^-$ groups. Iodine speciation in basalts therefore seems to reflect a trend amongst halogens, with lighter chlorine bonding to network modifying cations, and bromine changing affinity from network modifying cations to oxygen anions under pressure. In the absence of a fluid aqueous phase, iodine could thus reach the Earth’s surface in basaltic magmas as an oxide, not as a reduced species

Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor.

BACKGROUND: In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. METHODS AND RESULTS: We generated double-deficient mice for Mertk and Mfge8 (Mertk(-/-)/Mfge8(-/-)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk(-/-)), or Mfge8-deficient (Mfge8(-/-)) animals, Mertk(-/-)/Mfge8(-/-) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C(High and Low) monocytes and macrophages. In parallel, Mertk(-/-)/Mfge8(-/-) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C(High) and Ly6C(How) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C(High)/Ly6C(Low) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre(+)/VEGFA(fl/fl) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. CONCLUSIONS: After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart

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

Lutetium incorporation in magmas at depth:changes in melt local environment and the influence on partitioning behaviour

International audienceThe structure of two Lu doped (4000 ppm) model end member silicate liquids, a highly polymerised haplogranite (Si-Al-Na-K-O) and a less polymerised anorthite-diopside (Si-Al-Mg-Ca-O), have been studied up to 8 GPa using in situ x-ray diffraction techniques. The results are the first to identify trace rare Earth element incorporation in silicate melts at high pressure. At pressures below 5 GPa, the bonding environment of Lu-O was found to be dependent on composition with coordination number CN Lu−O = 8 and bond distance r Lu−O = 2.36Å36Å in the haplogranite melt, decreasing to CN Lu−O = 6 and r Lu−O = 2.29Å29Å in the anorthite-diopside melt. This compositional variance in coordination number at low pressure is consistent with observations made for Y-O in glasses at ambient conditions and is coincident with a dramatic increase in the partition coefficients previously observed for rare Earth elements with increasing melt polymerisation. With increasing pressure we find that CN Lu−O and r Lu−O remain constant in the haplo-granite melt. However, an abrupt change in both Lu-O coordination and bond distance is observed at 5 GPa in the anorthite-diopside melt, with CN Lu−O increasing from 6 to 8-fold and r Lu−O from 2.29 to 2.39Å39Å. This occurs over a similar pressure range where a change in the P-dependence in the reported rare Earth element partition coefficients is observed for garnet-, clinopyroxene-, and olivine-melt systems. This work shows that standard models for predicting trace elements at depth must incorporate the effect of pressure-induced structural transformations in the melt in order to realistically predict partitioning behaviour

Interleukin-23 receptor expressing γδ T cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice

Aims Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T-helper 17 cells) and gamma delta T cells, in atherosclerosis is only incompletely understood. Here, we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and gamma delta T cells in atherosclerosis. Methods and results IL-23R(+) cells were frequently found in the aortic root in contrast to the aorta in low-density lipoprotein receptor deficient IL-23R reporter mice (Ldlr(-/-)Il23r(gfp/+)), and mostly identified as gamma delta T cells that express IL-17 and GM-CSF. scRNA-seq confirmed gamma delta T cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr(-)(/)(-)Il23r(gfp/gfp) mice deficient in IL-23R showed a loss of IL-23R(+) cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr(-/-) controls after 6 weeks of high-fat diet feeding. In contrast, Ldlr(-/-)Tcr delta(-/-) mice lacking all gamma delta T cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr(-)(/-) mice. In both HFD-fed Ldlr(-/-)Il23r(gfp/gfp) and Ldlr(-/-)Tcr delta(-/-) mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators. Conclusions IL-23R(+) gamma delta T cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis, and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development

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