44
and differentiate into three subtypes of M2 macrophages. Several molecules have
been identifi ed as regulators of the switch from early pro-infl ammatory to late
anti- infl ammatory macrophage phenotypes. cAMP response element-binding pro-
tein (CREB), a multifunctional transcription factor, is critical for the up-regulation
of genes associated with M2 macrophages (IL-10, IL-13R, Arg-1) and repression
of M1 macrophage activation [ 54 ]. Mitogen-activated protein kinase (MAPK)
phosphatase- 1, through inhibition of p38 MAPK activation, functions to control
macrophage subtype shifting. MAPK also helps to resolve infl ammation to allow
for proper muscle repair [ 55 ]. Recently, AMP-activated protein kinase (AMPK) ,
widely known as a regulator of metabolic homeostasis, has also been identifi ed as
a regulator of macrophage polarization skewing. Mounier et al. [ 56 ], demonstrated
loss of M2 macrophage functionality and a loss of M2 markers expressed in
AMPKα 1 −/− macrophages. Further, AMPKα 1 −/− mice showed defi cient muscle
repair resulting from a failure of M1 macrophage phagocytosis-induced polariza-
tion to an M2 phenotype [ 56 ].
Fig. 3.2 Immune cell contribution and modulation in damaged muscle tissue. In response to myo-
fi ber injury, neutrophils from circulation invade the site of damage where they aid in further tissue
break down and recruit CX3CR1 Lo , Ly6C + , CCR2 + monocytes, differentiating into M1 macro-
phages , for continued debris clearance and pro-infl ammatory cytokine secretion. M1 phagocytosis
induces macrophage polarization towards an anti-infl ammatory phenotype to support muscle
repair. CX3CR1 Hi , Ly6C Lo , CCR2 − monocytes differentiate into M2a, M2b, and M2c macrophages,
functioning to suppress infl ammation and promote satellite cell proliferation and differentiation. T
regulatory cells assist M2 macrophages in resolving infl ammation and fostering muscle repair
C.A. Lynch et al.