Macrophages are a type of innate immune cell, and like all immune cells are involved in a great many processes in the body, ranging from tissue regeneration to clearing out molecular waste and debris to destruction of pathogens. Macrophages, and the similar microglia of the central nervous system, adopt different phenotypes, known as polarizations, depending on environment and the task at hand. The M1 polarization is pro-inflammatory and focused on ingestion of pathogens and debris, while the M2 polarization is anti-inflammatory and focused on regeneration. These are broad buckets and as such not truly representative of the real complexity of types and behaviors in these cell populations, but they are helpful enough for researchers to consider therapies based on forcing macrophages to preferentially adopt one polarization over another.
Earlier work on macrophage polarizations in aging suggested that issues arise with a growth in M1 populations and reduction in M2 populations, mirroring the rising chronic inflammation of aging. Matters are more complicated and tissue specific than that, however. To pick one illustrative example, today's open access commentary looks at what is known of polarization in the aging of muscle tissue, where the opposite trend is observed. The collective activities of cells, like cell metabolism itself, is a ferociously complicated domain and varies widely from tissue type to tissue type within the body. How these aspects of our biology change with age is yet another layer of complexity atop that, and little of it is completely mapped and understood at the detail level. Simple points of intervention, or global changes that can be made safely, are few and far between.
Macrophage function is largely mediated by a unique process of polarization. Depending on local environmental cues, macrophages polarize to pro-inflammatory M1 or anti-inflammatory M2 subtypes. In skeletal muscle, polarized macrophages regulate injury repair or infection resolution. Upon injury, infiltrated monocytes polarize to M1 and secrete proinflammatory cytokines to facilitate the elimination of pathogens and the cleanup of tissue debris. Subsequently, M2 macrophages that are converted from M1 and recruited from surrounding muscles jointly suppress inflammation and promote growth factors and collagen synthesis that contribute to injury repair. Accordingly, the blocking of the M1 to M2 transition resulted in defective repair, and the depletion of macrophages severely compromised muscle repair.
Contrary to muscle repair, the role of macrophage involvement in skeletal muscle aging is poorly understood. To gain insight into the function of macrophages in skeletal muscle aging, we analyzed their polarization status in aging human skeletal muscle. Considering that skeletal muscle aging inevitably occurs even in individuals devoid of obvious injury or infection, we studied resident macrophages from healthy older individuals in order to focus on normal/natural aging. We found that most macrophages in human skeletal muscle were M2, and the number increased with age. In contrast, M1 macrophages were much fewer in number, and decreased with age.
We further observed that macrophages closely co-localize with adipocytes in intermuscular adipose tissue (IMAT), but not satellite cells (muscle stem cells). This co-localization suggested possible mechanisms for the M2 increase and the actions of increased M2 in aging skeletal muscle. Adipocytes have been shown to secrete M2-promoting Th2 cytokines and adiponectin, and M2 was indeed the major macrophage population in adipose tissues in lean but not obese mice. We infer that adipocytes in IMAT contribute to the extensive M2 polarization in normal skeletal muscle, and that increased IMAT in aging skeletal muscle in non-obese, healthy people may be responsible for the M2 increase.
In keeping with the evidence that M2 macrophages are capable of regulating collagen synthesis and adipogenesis, we observed that collagen mRNA levels were dramatically reduced in aged mouse skeletal muscle, but collagen protein levels were comparable between aged and young muscle. We inferred from this observation that increased M2 macrophages may contribute to the stable collagen protein level in muscle. Consistent with this notion, increased M2 macrophages in aged skeletal muscle were shown to promote muscle fibrosis in mice.
Regarding adipogenesis, a recent study showed that M2 macrophages suppress adipocyte progenitor cell proliferation in mouse adipose tissue, and that the depletion of M2 macrophages enhanced the generation of small adipocytes and improved insulin sensitivity. In skeletal muscle, it was shown that M2 macrophages elevate adipogenesis by fibro-adipogenic progenitors (FAPs)/ncb2015">fibro-adipogenic progenitors (FAPs). Thus, increased M2 macrophages may contribute to fibrosis and fat infiltration, the two major features of skeletal muscle aging, although their exact function remains elusive.