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Wednesday, August 11, 2010

Muscle Repair

I found a paper I really like:

A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repairDaniela Ruffell1, Foteini Mourkioti1, Adriana Gambardella1, Peggy Kirstetter, Rodolphe G. Lopez, Nadia Rosenthal and Claus Nerlov2
+ Author Affiliations

Mouse Biology Unit, European Molecular Biology Laboratory, Via Ramarini 32, 00015 Monterotondo, Italy
Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved August 24, 2009

↵1D.R., F.M., and A.G. contributed equally to this work. (received for review July 31, 2009)

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.

macrophage polarizationmuscle regenerationtranscription
2To whom correspondence should be addressed. E-mail: nerlov@embl.itAuthor 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.

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