Exploring the Molecular Mechanisms that Regulate Macrophage Polarization

Macrophages are tissue-resident innate phagocytes that exhibit remarkable functional plasticity. They can dynamically tune their phenotype in response to the changing combination of cytokines and pathogen-associated molecular patterns (PAMPs) present during an infection. Macrophages can switch from a pro-inflammatory, highly phagocytic state (M1) at the beginning of an infection, which allows for the efficient clearance of invading microbes, to an anti-inflammatory, repair state (M2) at its resolution. These shifts in phenotype are driven by the altered expression of >1,000 genes, largely controlled by a core set of transcriptional regulators, which include the NF-κB, STAT, and IRF transcription factor families. For this reason, these transcription factors and the signaling pathways that control their activity are targeted by pathogens as part of immune evasion strategies. For example, Toxoplasma gondii and Listeria moncytogenes both suppress the M1 polarization of host macrophages by inhibiting IFNγ-STAT1 signaling, thereby decreasing their antimicrobial activity. However, macrophages are not defenseless against this mode of immunomodulation, as infection with these pathogens also stimulates the expression of host factors that partially counteract these effects. As altered macrophage polarization plays an important role in the pathophysiology of numerous human diseases, lessons learned through studying its modulation in infection may have broader ramifications for our understanding of cancer, chronic inflammatory disorders, and other conditions.

This Research Topic aims to gather the latest information on how the transition between macrophage polarization states is controlled during infection and how this is impacted by both pathogen- and host-derived modulators. By doing so, we hope to elucidate the interplay between these modulators and their different modes of action. To this end we welcome the submission of Original Research, Reviews, Mini-Reviews, and Methods articles that cover but are not limited to the following:
• New insights into the control of M1 and M2-associated gene expression by transcriptional regulators and co-regulators
• Modulation of macrophage NF-κB and STAT signaling during infection
• Mechanisms of pathogen-induced macrophage repolarization
• Mechanisms by which macrophages counteract immunomodulation by (intracellular) pathogens