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

Daniela Ruffell, Foteini Mourkioti, Adriana Gambardella, Peggy Kirstetter, Rodolphe G Lopez, Nadia A Rosenthal, Claus Nevlov

Research output: Contribution to journalArticleResearchpeer-review

348 Citations (Scopus)

Abstract

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 ( beta-delta Cre) 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/EBP beta cascade leading to muscle repair is muscle-extrinsic. While beta-delta Cre 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.
Original languageEnglish
Pages (from-to)17475 - 17480
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number41
DOIs
Publication statusPublished - 2009
Externally publishedYes

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