Plasticity of monocytes/macrophages: phenotypic changes during disease progression

Abstract

Macrophage is a key component of innate immunity that exhibit extensive plasticity and heterogeneity. They are present in virtually every organ of the body and can be replenished by circulating monocytes following insults. Originally macrophages were divided into two major phenotypes: pro-inflammatory M1, which is initiated by TNF-α, INF-γ, and bacterial components such as lipopolysaccharide (LPS), and anti-inflammatory M2, which is activated through stimulation of IL-4, IL-10, and IL-13. However, segregation into two distinct phenotypes is a marked simplification of the in vivo reality and it is now widely accepted that macrophage phenotype is plastic and determined by highly complex microenvironments, and therefore likely more accurately considered as a spectrum of possible forms of activation. Numerous studies have documented flexibility in their programming, with macrophages switching from one functional phenotype to another in response to the variable microenvironmental signals of the local milieu. Various macrophage populations exist that play distinct and non-redundant roles in fibrosis, tissue repair, and regeneration. For instance, in a general wound healing process, embryo-derived tissue-resident macrophages are rapidly replaced by monocytes after the initial injury. These monocyte-derived macrophages play an active role in the early initiation of acute inflammation. As early as 24–72 h upon tissue injury, macrophage function changes toward an anti-inflammatory phenotype that promotes cell proliferation and tissue remodeling. Upon resolution of inflammation, steady-state self-maintenance of macrophages is also recovered. The wound microenvironment has a predominant role in the behavior and functionality of cells. Both mouse and human diabetic wound preferably induce persistent proinflammatory macrophage polarization that contributes to chronic, non-healing wounds. Contrastingly, prolonged activation of M2 macrophages can also lead to excessive wound healing and ultimately fibrosis. In the context of cancer, anti-inflammatory macrophages have been associated with tumor progression and immunosuppression, thereby negatively affecting the prognosis of patients. On the other hand, studies also showed that the phenotypical changes of macrophages are also accompanied by changes in glycolysis and mitochondrial-related genes as well. Classically activated, proinflammatory M1 macrophages depend to a large extent on glycolysis and produce lactate as the tricarboxylic acid cycle is blocked at two steps. Alternatively, activated M2 macrophages prefer β-oxidation and oxidative phosphorylation to synthesize ATP. However, the number and diversity of signals and the magnitude of the response required to switch macrophages into a pro or anti-inflammatory state remain unclear. A number of techniques have been developed over the years to identify and visualize cell populations, uncover regulatory relationships between genes, and track the trajectories of distinct cell lineages in development. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies. Understanding and being able to controllable promote the desired macrophage phenotypes could have a significant impact on a wide range of diseases.