An evolutionary perspective of macrophages in host defense against intracellular pathogens

Macrophages are crucial for the proper defense of the host. These cells survey tissues of the body and perform vital functions in homeostasis such as phagocytosing cellular debris and nutrient resorption, as well as in defense against infection by phagocytosing microbes. This constant sampling of their microenvironment position these cells to transduce environmental cues into an appropriate tissue response. This mechanism clearly lends itself to immune surveillance. Macrophages are capable immune cells and can employ numerous parallel strategies to eliminate pathogens that are phagocytosed. To prevent pathogens from taking residence in the cytosol of the macrophage, these cells can activate regulated cell death. This process initiates a cell death program that eliminates the host cell in an altruistic manner to protect the host. Macrophages effectively activate pyroptosis, one form of these regulated cell death programs that is unique in that it releases processed cytokines to activate an immune response in the surrounding tissue. This process activates in response to the detection of pathogen activity in the cytosol, and signals through a multiprotein complex called the inflammasome. This process is conserved in phagocytes in organisms with at least a distant common ancestor as coral, demonstrating that the battle between pathogen and host for control of the cytosol is an ancient one. The mechanisms by which intracellular macrophage immunity occurs have remained remarkably similar, yet demonstrate surprising changes across species that may help guide future studies into how to best manage this battle in human disease.