Expression et fonction de la NOS neuronale dans les cellules musculaires lisses de la paroi vasculaire

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Exposure to low to moderate doses of ionizing radiation induces a reduction of pro-inflammatory Ly6Chigh monocytes and a U-curved response of T cells in ApoE -/- mice

International audienceLow dose ionizing radiation (LDIR) is known to have a protective effect on atherosclerosis in rodent studies, but how it impacts different cells types involved in lesion formation remains incompletely understood. We investigated the immunomodulatory response of different doses and dose-rates of irradiation in ApoE mice. Mice were exposed to external γ rays at very low (1.4 mGy.h-1) or low (50 mGy.h-1) dose-rates, with cumulative doses spanning 50 to 1000 mGy. Flow cytometry of circulating cells revealed a significant decrease in pro-inflammatory Ly6CHi monocytes at all cumulative doses at low dose-rate, but more disparate effects at very low dose-rate with reductions in Ly6CHi cells at doses of 50, 100 and 750 mGy only. In contrast, Ly6CLo monocytes were not affected by LDIR. Similarly, proportions of CD4+ T cell subsets in the spleen did not differ between irradiated mice and non-irradiated controls, whether assessing CD25+FoxP3+ regulatory or CD69+ activated lymphocytes. In the aorta, gene expression of cytokines such as IL-1 and TGF-ß and adhesion molecules such as E-Selectin, ICAM-1, and VCAM-1 were reduced at the intermediate dose of 200 mGy. These results suggest that LDIR may reduce atherosclerotic plaque formation by selectively reducing blood pro-inflammatory monocytes and by impairing adhesion molecule expression and inflammatory processes in the vessel wall. In contrast, splenic T lymphocytes were not affected by LDIR. Furthermore, some responses to irradiation were nonlinear; reductions in aortic gene expression were significant at intermediate doses, but not at either highest or lowest doses. This work furthers our understanding of the impact of LDIR with different dose-rates on immune system response in the context of atherosclerosis

Effects of low dose radiation on atherosclerosis in APOE(-/-) mice: study of short term effects on macrophage polarization

International audienceAthersoclerosis is a chronic inflammatory disease of medium and large arteries that can lead to myocardial infarction or stroke. Mechanistic understanding of the effects of low-dose ionizing radiation (LDIR) on atherosclerosis remains incomplete. The experimental studies have shown a protective effect of LDIR on atherosclerosis in rodent models. However early responses of LDIR in different cell types that are known to be involved in atherosclerosis is not clear. The objective is to understand biological mechanisms of LDIR include on animal groups with multimodal approach. In this study, we report results of applying the foldchange, usually considered a relevant criterion for stating difference and similarity between measurements and a multilevel multivariate approach. Revealing complex correlations and causal links related to health conditions, such as atherosclerosis, can help advance the concept adverse outcome pathway (AOP)

Gas6 promotes inflammatory (CCR2hiCX3CR1lo) monocyte recruitment in venous thrombosis

Objective - Coagulation and inflammation are inter-related. Gas6 (growth arrest-specific 6) promotes venous thrombosis and participates to inflammation through endothelial-innate immune cell interactions. Innate immune cells can provide the initiating stimulus for venous thrombus development. We hypothesize that Gas6 promotes monocyte recruitment during venous thrombosis. Approach and Results - Deep venous thrombosis was induced in wild-type and Gas6-deficient (-/-) mice using 5% FeCl and flow reduction in the inferior vena cava. Total monocyte depletion was achieved by injection of clodronate before deep venous thrombosis. Inflammatory monocytes were depleted using an anti-C-C chemokine receptor type 2 (CCR2) antibody. Similarly, injection of an anti-chemokine ligand 2 (CCL2) antibody induced CCL2 depletion. Flow cytometry and immunofluorescence were used to characterize the monocytes recruited to the thrombus. In vivo, absence of Gas6 was associated with a reduction of monocyte recruitment in both deep venous thrombosis models. Global monocyte depletion by clodronate leads to smaller thrombi in wild-type mice. Compared with wild type, the thrombi from Gas6 mice contain less inflammatory (CCR2CXCR1) monocytes, consistent with a Gas6-dependent recruitment of this monocyte subset. Correspondingly, selective depletion of CCR2CXCR1 monocytes reduced the formation of venous thrombi in wild-type mice demonstrating a predominant role of the inflammatory monocytes in thrombosis. In vitro, the expression of both CCR2 and CCL2 were Gas6 dependent in monocytes and endothelial cells, respectively, impacting monocyte migration. Moreover, Gas6-dependent CCL2 expression and monocyte migration were mediated via JNK (c-Jun N-terminal kinase). Conclusions - This study demonstrates that Gas6 specifically promotes the recruitment of inflammatory CCR2CXCR1 monocytes through the regulation of both CCR2 and CCL2 during deep venous thrombosis