Macrophage fate: to kill or not to kill?

Abstract

Macrophages are dynamic innate immune cells that either reside in tissue, serving as sentinels, or recruited as monocytes from bone marrow into inflamed and infected tissue. In response to cues in the tissue microenvironment (TME), macrophages polarize on a continuum toward M1 or M2 with diverse roles in progression and resolution of disease. M1-like macrophages exhibit proinflammatory functions with antimicrobial and anti-tumorigenic activities, while M2-like macrophages have anti-inflammatory functions that generally resolve inflammatory responses and orchestrate a tissue healing process. Given these opposite phenotypes, proper spatiotemporal coordination of macrophage polarization in response to cues within the TME is critical to effectively resolve infectious disease and regulate wound healing. However, if this spatiotemporal coordination becomes disrupted due to persistent infection or dysregulated coagulation, macrophages' inappropriate response to these cues will result in the development of diseases with clinically unfavorable outcomes. Since plasticity and heterogeneity are hallmarks of macrophages, they are attractive targets for therapies to reprogram toward specific phenotypes that could resolve disease and favor clinical prognosis. In this review, we discuss how basic science studies have elucidated macrophage polarization mechanisms in TMEs during infections and inflammation, particularly coagulation. Therefore, understanding the dynamics of macrophage polarization within TMEs in diseases is important in further development of targeted therapies.