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CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair

Ruffell, Daniela ; Mourkioti, Foteini ; Gambardella, Adriana ; Kirstetter, Peggy ; Lopez, Rodolphe G ; Rosenthal, Nadia ; Nerlov, Claus

Proceedings of the National Academy of Sciences - PNAS, 2009-10, Vol.106 (41), p.17475-17480 [Periódico revisado por pares]

National Academy of Sciences

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  • Título:
    CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair
  • Autor: Ruffell, Daniela ; Mourkioti, Foteini ; Gambardella, Adriana ; Kirstetter, Peggy ; Lopez, Rodolphe G ; Rosenthal, Nadia ; Nerlov, Claus
  • Assuntos: Antiinflammatories ; B lymphocytes ; Biological Sciences ; Gene expression ; Genes ; Macrophages ; Muscle tissues ; Muscles ; Phenotypes ; Regeneration ; Tissue repair
  • É parte de: Proceedings of the National Academy of Sciences - PNAS, 2009-10, Vol.106 (41), p.17475-17480
  • Notas: Author contributions: D.R., F.M., A.G., N.R., and C.N. designed research; D.R., F.M., A.G., and P.K. performed research; R.G.L. generated conditional Cebpb KO mice; D.R., F.M., A.G., P.K., and C.N. analyzed data; and N.R. and C.N. wrote the paper.
    1D.R., F.M., and A.G. contributed equally to this work.
    Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 24, 2009
  • Descrição: Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected. Mice carrying the mutated Cebpb promoter (βΔCre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBPβ cascade leading to muscle repair is muscle-extrinsic. While βΔCre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb, leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.
  • Editor: National Academy of Sciences
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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