Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways

Abstract

Monocytes/macrophages are heterogeneous and versatile cells that could undergo their phenotypically/functionally dynamic switch in response to the microenvironment signals. Two major macrophage subpopulations with different functions which represent extreme of a continuum in a universe of activation states, including classically activated/inflammatory (M1) and alternatively activated/regenerative (M2) macrophages, have long been recognized. Emerging evidence through genetic or pharmacologic approaches has now been made in defining the actual fate in vivo and in vitro underlying M1 or M2-like polarized activation under physiological and pathological conditions. These cells are characterized by their expression of cell surface markers, secreted cytokines and chemokines, and transcription and epigenetic pathways. Here in this review, we shed new light on the contribution of several major signaling pathways and their modulators/targets involved in directing the macrophage plasticity and polarized function, assess the mechanisms of macrophage polarization by interacting endogenous cellular mechanisms and molecules associated with reciprocal skewing of macrophage polarization between the M1 and M2 states. The identification of mechanisms underlying functional polarization of macrophages into M1 or M2 cells might provide new insights into a basis for macrophage-centered diagnostic and therapeutic strategies for multiple diseases.

Keywords: ACE; AMP-activated protein kinase; AMPK; AP-1; AT1; ATMs; Adipose tissue macrophages; Arg-1; BMDM; C-Jun N-terminal kinases; C/EBP; CAAT/enhancer-binding proteins; CCR2; CM; Cellular signaling pathway; C–C motif chemokine receptor 2; GM-CSF; HFD; HMDM; IRF; JNKs; KCs; LPS; M-CSF; MAPKs; MLK3; Macrophage polarization; MicroRNAs; NAFLD; NICD; Notch intracellular domain; PBMC; PI3K; PPAR; Phenotypic switch; SLE; SOCS; STAT; TAMs; TLR; Toll-like receptor; activator protein-1; angiotensin type 1; angiotensin-converting enzyme; arginine-1; bone marrow-derived macrophages; conditioned medium; granulocyte-macrophage colony-stimulating factor; high-fat diet; human monocyte-differentiated macrophage; iNOS; inducible nitric oxide synthase; interferon regulatory factor; kupffer cells; lipopolysaccharide; macrophage CSF; miR; microRNA; mitogen-activated protein kinases; mixed-lineage kinase 3; nonalcoholic fatty liver disease; peripheral blood monocytes; peroxisome proliferator-activated receptor; phosphatidylinositol-3-kinase; signal transducers and activators of transcription; suppressor of cytokine signaling; systemic lupus erythematosus; tumor-associated macrophages.