Macrophages as Both Friends and Foes in Age-Related Diseases

Macrophages are cells of the innate immune system, found throughout the body, and which play a great many roles beyond the obvious ones of defending against invading pathogens. They destroy cancerous and senescent cells, ingest molecular waste and debris between cells, and participate in the processes of tissue regeneration and maintenance, to pick a few examples. Further, the immune system of the brain includes an analogous population of cells known as microglia, which additionally take on supporting roles essential to the proper functioning of neurons and their synaptic connections.

Chronic inflammation is important in the progression of age-related diseases, and as a part of the immune system macrophages are very much involved in inflammation. This is a two-way street; greater inflammatory signaling in the environment will tend to make macrophages adopt a more aggressive behavior, adding their own inflammatory signaling to the mix. Equally, macrophages that become inflammatory for other reasons can rouse greater and broader inflammation via their actions. This is particularly true for senescent microglia, which appear quite important in a number of age-related conditions.

Setting aside cellular senescence, macrophage behavior can be loosely divided into phenotypes known as polarizations. M1 macrophages are inflammatory and focused on attacking pathogens, while M2 macrophages are anti-inflammatory and focused on regeneration. This is a useful categorization, while recognizing that it perhaps oversimplifies the reality of a continuous distribution of behaviors, not a pair of widely separate states. Some aspects of aging are associated with a shift in populations to favor M1 over M2, but this is not universal. Nonetheless, a number of research groups are working to find ways to bias macrophages to one polarization over another, to turn their contribution from harmful to helpful.

Targeting Macrophages: Friends or Foes in Disease?

Macrophages occupy a prominent position during immune responses. They are considered the final effectors of any given immune response since they can be activated by a wide range of surface ligands and cytokines to acquire a continuum of functional states. Macrophages are involved in tissue homeostasis and in the promotion or resolution of inflammatory responses, causing tissue damage or helping in tissue repair.

Knowledge in macrophage polarization has significantly increased in the last decade. Biomarkers, functions, and metabolic states associated with macrophage polarization status have been defined both in murine and human models. Moreover, a large body of evidence demonstrated that macrophage status is a dynamic process that can be modified. Macrophages orchestrate virtually all major diseases – sepsis, infection, chronic inflammatory diseases (rheumatoid arthritis), neurodegenerative disease, and cancer – and thus they represent attractive therapeutic targets. In fact, the possibility to “reprogram” macrophage status is considered as a promising strategy for designing novel therapies.

Macrophages are widely distributed throughout the tissues and display a huge functional heterogeneity. They can acquire pro- or anti-inflammatory functions depending on the surrounding cytokines and tissue microenvironment. Macrophages have been classified according to a linear scale, on which M1 macrophages represent one extreme and M2 macrophages represent the other.

Macrophage polarization is plastic and reversible. While M1 polarization takes place at the initial stages of the inflammatory response, M2 polarization is predominant during resolution of inflammation. The sequential occurrence of both polarization states is an absolute requirement for the appropriate termination of inflammatory responses, as well as for adequate tissue repair after injury, and alterations in the shift between macrophage polarization states result in chronic inflammatory pathologies, autoimmune diseases, and even metabolic disorders. We believe that targeting macrophage polarization might lead to novel intervention strategies.

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