Macrophages are well-known defense cells of the immune system, responsible for utilizing the cellular breakdown process of phagocytosis to digest pathogens and cellular debris. In a new study, researchers identify a novel, not-so-well-known pathway responsible for macrophage identity and expansion. Commandeering this pathway may help researchers manipulate the lives of macrophages to improve disease treatments.
If the immune system is a military defense system, then macrophages are the pacing guards primed to target any invader at first glance. Macrophages are vital for homeostasis via phagocytosis of dead and dying cells. Macrophages also act as antigen-presenting cells recruited via the inflammatory response, and they act also as independent immune cells in injured organs when a swift and effective response is needed.
The macrophages at the center of this new finding are particularly those that live in serous cavities that line and protect important organs, playing important roles in disease prevention such as cancer and heart attack. Findings from the new study may help researchers improve prevention in these cases by altering the way macrophages develop and grow.
Serous cavity-dwelling macrophages may take up residence in one of three serous membranes:
"In recent years, work from many groups has changed the understanding of the hemopoietic origin and regulation of macrophages,” explained study coordinator Dr. Mercedes Ricote. “These studies have revealed enormous heterogeneity among tissue macrophages, depending on their embryonic or hemopoietic origin and on the miroenvironmental signals that modulate their identity and maintenance in adult life."
During the study, researchers explored how macrophages in serous cavities develop and expand after birth and are maintained throughout adulthood. They found that a nuclear receptor, retinoid X receptor (RXR), is largely responsible for regulating serous cavity macrophage development. RXRs live inside cells, sensing nearby lipids and vitamin A derivatives involved in RXR activation. This activation is the switch that “turns on” gene expression necessary for key physiological functions: development, immunity, homeostasis, and metabolism.
Researchers studied the activity of RXR in a newborn mouse model, discovering that RXR is a necessary part of the pipeline that produces serous cavity macrophages, their continuous proliferation, and their ultimate survival in adulthood. When RXR is missing from this pipeline, toxic lipids aggregate and kill cells via apoptosis, a process of programmed cell death.
Further, in a mouse model of ovarian cancer, researchers observed peritoneal macrophages actually supporting tumor growth, highlighting an opportunity for RXR manipulation to reduce macrophage populations in this destructive context.