PMID: identifiant
de la référence Pubmed : |
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 (19079608)  |
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Modulation of macrophage activation state protects tissue from necrosis during critical limb ischemia in thrombospondin-1-deficient mice. |
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| auteur(s) : |
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Nicolas Bréchot1, Elisa Gomez1, Marine Bignon1, J. Khallou-Laschet2, M. Dussiot2, Aurélie Cazes1, Cécile Alanio-Bréchot3, Mélanie Durand1, Josette Philippe1, Jean-Sébastien Sylvestre4, Nico Van Rooijen5, Pierre Corvol1, Antonino Nicoletti2, Bénédicte Chazaud6, Stéphane Germain ( ) 1, 7 |
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| laboratoire : |
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| titre abrégé : |
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Macrophage polarization in CLI |
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| résumé : |
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BACKGROUND: Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI. METHODS AND FINDINGS: Using a genetic model of tsp-1(-/-) mice subjected to femoral artery excision, we report that tsp-1(-/-) mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1(-/-) and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1(-/-) mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1(-/-) mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1(-/-) mice, thereby demonstrating that macrophages mediated tissue protection in these mice. CONCLUSION: This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia. |
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| domaine : |
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Sciences du Vivant/Médecine humaine et pathologie/Cardiologie et système cardiovasculaire
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langue du texte
intégral : |
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Anglais |
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| ISSN : |
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1932-6203 |
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| type de publication : |
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Articles dans des revues avec comité de lecture |
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| DOI : |
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10.1371/journal.pone.0003950 |
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| Audience : |
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internationale |
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| date de publication : |
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2008 |
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date de publication
électronique : |
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16/12/2008 |
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| volume : |
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3 |
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| numéro : |
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12 |
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| page, identifiant, ... : |
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e3950 |
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