Molecular Mechanisms Modulating the Phenotype of Macrophages and Microglia

Abstract

Macrophages and microglia play crucial roles during central nervous system development, homeostasis and acute events such as infection or injury. The diverse functions of tissue macrophages and microglia are mirrored by equally diverse phenotypes. A model of inflammatory/M1 versus a resolution phase/M2 macrophages has been widely used. However, the complexity of macrophage function can only be achieved by the existence of varied, plastic and tridimensional macrophage phenotypes. Understanding how tissue macrophages integrate environmental signals via molecular programs to define pathogen/injury inflammatory responses provides an opportunity to better understand the multilayered nature of macrophages, as well as target and modulate cellular programs to control excessive inflammation. This is particularly important in MS and other neuroinflammatory diseases, where chronic inflammatory macrophage and microglial responses may contribute to pathology. Here, we perform a comprehensive review of our current understanding of how molecular pathways modulate tissue macrophage phenotype, covering both classic pathways and the emerging role of microRNAs, receptor-tyrosine kinases and metabolism in macrophage phenotype. In addition, we discuss pathway parallels in microglia, novel markers helpful in the identification of peripheral macrophages versus microglia and markers linked to their phenotype.

Melatonin in macrophage biology: Current understanding and future perspectives

“…Exosomes can change macrophage phenotypes; hence, it will be interesting to study whether exosomes (especially exosomal cargos such as miRNAs, lncRNAs and metabolites) are associated with melatonin‐mediated macrophage polarization. Besides, it will be worth to explore the interactions between melatonin and other classic molecular regulators (eg, c‐MYC), which mediate macrophage phenotypes . Another melatonin‐related player to be considered in the future is SIRT1, which is upregulated in nontumor cells by melatonin and shares with melatonin several anti‐inflammatory properties by inhibiting or downregulating several factors discussed in this review, such as HMGB1, TLR4, mTORC1, NLRP3, and NF‐κB, as recently summarized .…”

“…It is of necessity to note that miRNAs (eg, miR‐155 and miR‐146) are also involved in macrophage polarization . MiR‐155 is the most highly upregulated miRNA in LPS/IFN‐γ‐treated macrophages .…”

“…Physiological functions of macrophages go from host defense to immune downregulation, in addition to their homeostatic activities . Indeed, macrophages are of high diversity and plasticity and can polarize into different phenotypes to exert diverse functions . Environmental signals, cellular signaling pathways, cellular or exosomally transmitted microRNAs (miRNAs), and metabolic sensors contribute to macrophage polarization, which is an emerging field that attracts increasing attention.…”

“…Indeed, macrophages are of high diversity and plasticity and can polarize into different phenotypes to exert diverse functions . Environmental signals, cellular signaling pathways, cellular or exosomally transmitted microRNAs (miRNAs), and metabolic sensors contribute to macrophage polarization, which is an emerging field that attracts increasing attention. Interestingly, the functions of macrophages can be modulated by melatonin .…”

Autophagy in Inflammation: the p38α MAPK-ULK1 Axis

“…Accumulating evidence suggests that microphage and microglia acquire different activation states to modulate their cellular functions under different contexts [21] . Upon activation to the M1 phenotype, macrophage and microglia release pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses.…”