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

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 (␤⌬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␤ cascade leading to muscle repair is muscle-extrinsic. While ␤⌬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.macrophage polarization ͉ muscle regeneration ͉ transcription

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

“…CEBPB is also important in macrophage function, which plays a crucial role in normal skeletal muscle repair (Rahman et al ., 2012). In addition, expression of CEBPB in blood leukocytes has been positively associated with muscle strength in humans, further supporting the possible link between gene variants and a decline in skeletal muscle function in older age groups (Ruffell et al ., 2009). …”

Cell death, clearance and immunity in the skeletal muscle

“…75 'Alternatively activated' or 'M2' macrophages predominate during the resolution phases of the damage when they regulate the termination of the inflammatory responses. 69,76 Monocyte-derived macrophages undergo dynamic transitions between M1 and M2 and this timely transition is increasingly felt to be the key to muscle homeostasis. 77,78 MAP kinase phosphatase-1 (MKP-1) regulates cell remnant disposal, macrophage transition and muscle healing.…”

“…Debris are effectively cleared but muscle fiber regeneration is severely jeopardized. 76 In contrast, other crucial pathways, such as those coordinated by myeloid hypoxia-inducible factors, are apparently dispensable for M1/M2 shift and muscle healing after sterile injury. 82 Of importance, other cells, including eosinophils and FAPs, are apparently involved in the clearance of necrotic muscle debris in experimental models 56,83 (Figure 2).…”

Inflammation et régénération musculaire

“…La sécrétion du facteur de croissance IGF-1 (insulin growth factor-1) par les macrophages anti-inflammatoires permet également de stimuler la croissance des fibres musculaires en activant la voie de signalisation Akt-1 (protéine kinase B ou PKB) qui promeut la synthèse protéique et diminue la dégradation des protéines [22]. In vivo, un modèle de souris transgéniques, déficientes pour l'activation du facteur de transcription C/EBPb (CCAAT-enhancer-binding protein) chez lesquelles la transition des macrophages vers le phé-notype anti-inflammatoire est inhibée, a montré que le nettoyage des débris tissulaires n'est pas affecté en l'absence des macrophages anti-inflammatoires, mais que la différenciation des myoblastes et la croissance des fibres musculaires étaient déficientes [23]. Il est important de noter que les phases pro-et anti-inflammatoires peuvent se chevaucher, les différentes sous-populations de macrophages se retrouvant alors au même instant au niveau de la même zone régénérative [24,25].…”