Bistability in macrophage polarization and metabolic implications

Abstract

Macrophages are essential innate immune cells characterized by a high diversity and plasticity. In vitro, their full dynamic range of activation profiles include the classical pro-inflammatory (M1) and the alternative anti-inflammatory (M2) program. Bistability usually arises in biological systems that contain a positive-feedback loop or a mutually inhibitory, double-negative-feedback loop, which are common regulatory motifs reported for macrophage transitions from one activation state to the other one. This switch-like behavior of macrophage is observed at four different levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1 and NF-KB/p50-p65) and M2 (STAT3 and NF-KB/p50-p50) signaling pathways. Second, a switch-like behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, those changes impact metabolic gene expression leading to several switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis and nitrogen metabolism. Fourth, metabolic changes are monitored by specialized metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining the signals to promote either M1 or M2 activation. The targeting of robust molecular switches has the potential to treat a broad range of widespread diseases such as sepsis, cancer or chronic inflammatory diseases.

Cell state transition analysis identifies interventions that improve control ofM. tuberculosisinfection by susceptible macrophages

“…The activation of appropriate effector mechanisms by macrophages is orchestrated by pathogen-derived ligands, cytokines produced by T lymphocytes, and other immune and stromal cells within the inflammatory milieu. Ideally, these signals induce activated macrophage states optimal for the pathogen elimination 17 . However, a number of the so-called intracellular pathogens survive inside macrophages and use them as a protected niche for the pathogen’s persistence and replication 18 .…”