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CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production.

ABSTRACT: Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2(-/-) mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that Apolipoprotein E (ApoE) is upregulated in mice with efficient regeneration. ApoE treatment enhances phagocytosis by mononuclear phagocytes in vitro, and restores phagocytic activity and muscle regeneration in Ccl2(-/-) mice. Because CX3CR1 deficiency may compensate for defective CCL2-dependant monocyte recruitment by modulating ApoE-dependent macrophage phagocytic activity, targeting CX3CR1 expressed by macrophages might be a powerful therapeutic approach to improve muscle regeneration.

SUBMITTER: Arnold L

PROVIDER: S-EPMC4686853 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production.

Arnold Ludovic L Perrin Hélène H de Chanville Camille Baudesson CB Saclier Marielle M Hermand Patricia P Poupel Lucie L Guyon Elodie E Licata Fabrice F Carpentier Wassila W Vilar José J Mounier Rémi R Chazaud Bénédicte B Benhabiles Nora N Boissonnas Alexandre A Combadiere Béhazine B Combadiere Christophe C

Nature communications 20151203

Muscle injury triggers inflammation in which infiltrating mononuclear phagocytes are crucial for tissue regeneration. The interaction of the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axis that guides phagocyte infiltration is incompletely understood. Here, we show that CX3CR1 deficiency promotes muscle repair and rescues Ccl2(-/-) mice from impaired muscle regeneration as a result of altered macrophage function, not infiltration. Transcriptomic analysis of muscle mononuclear phagocytes reveals that ...[more]

PMID: 26632270

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Project description:Coronary heart disease is associated with monocytosis. Studies using animal models of monocytosis and atherosclerosis such as ApoE(-/-) mice have shown bone marrow (BM) hematopoietic stem and multipotential progenitor cell (HSPC) expansion, associated with increased cell surface expression of the common ? subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor (CBS) on HSPCs. ApoE(-/-) mice also display increased granulocyte macrophage colony-stimulating factor-dependent monocyte production in the spleen. We investigated the role of the CBS in cholesterol-driven HSPC expansion, monocytosis, and atherosclerosis.Ldlr(-/-) mice were transplanted with ApoE(-/-)Cbs(-/-) or ApoE(-/-) BM followed by Western-type diet feeding. Compared with ApoE(-/-) BM-transplanted controls, ApoE(-/-)Cbs(-/-) BM-transplanted mice had reduced BM and splenic HSPC proliferation, fewer blood monocytes and neutrophils, and reduced macrophage content and area of early atherosclerotic lesions. More advanced lesions showed diminished macrophage and collagen content; however, lesion size was unchanged, reflecting an increase in necrotic core area, associated with a marked decrease in Abcg1 expression and increased macrophage apoptosis. Compared with wild-type mice, Western-type diet-fed ApoE(-/-) mice showed increased CBS expression on granulocyte macrophage colony-stimulating factor-producing innate response activator B cells and expansion of this population. ApoE(-/-)Cbs(-/-) BM-transplanted Ldlr(-/-) mice showed a marked decrease in innate response activator B cells compared with ApoE(-/-) BM-transplanted Ldlr(-/-) controls.Increased levels of CBS on HSPCs and splenic innate response activator B cells lead to expansion of these populations in ApoE(-/-) BM-transplanted Ldlr(-/-) mice, contributing to monocytosis and increased lesional macrophage content. However, in more advanced lesions, the CBS also has a role in atherosclerotic plaque stabilization.

Dataset Information

CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production.

Publications

CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production.

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