Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis

Abstract

Inflammation must be tightly regulated to both defend against pathogens and restore tissue homeostasis. The resolution of inflammatory responses is a dynamic process orchestrated by cells of the immune system. Macrophages, tissue-resident innate immune cells, are key players in modulating inflammation. Here, we review recent work highlighting the importance of macrophages in tissue resolution and the return to homeostasis. We propose that enhancing macrophage pro-resolution functions represents a novel and widely applicable therapeutic strategy to dampen inflammation, promote repair, and restore tissue integrity and function.

Keywords: SARS-CoV-2; efferocytosis; fibrosis; inflammation; macrophages; tissue repair.

Figure 1.. Pro-inflammatory and pro-resolution functions of macrophages.

Following exposure to an inflammatory trigger (e.g. infection), macrophages can respond by 1) promoting leukocyte recruitment to the site of infection through secretion of chemokines and other cytokines; 2) activating the vascular endothelium through TNFα secretion which can aid in leukocyte entry; 3) activating leukocytes, including NK cells, T cells, and B cells, through the secretion of cytokines such as TNFα, IL-6, IL-12, and IL-1β; and 4) participating in the activation of the adaptive immune system through antigen presentation and cytokine production. Macrophages help resolve inflammation by 1) producing anti-inflammatory factors such as IL-10 and TGF-β [53]; 2) clearing dead cells [25]; 3) inhibiting leukocyte recruitment through mechanisms such as MMP secretion [14]; 4) promoting tissue repair through production of growth factors and remodeling of the ECM [3]. IFN-I, type I interferons; TNFα, tumor necrosis factor alpha; TGF-β, transforming growth factor beta; MMPs, matrix metalloproteinases; GFs, growth factors; AREG, amphiregulin; IGF-1, insulin-like growth factor 1; PDGF, platelet-derived growth factor; ECM, extracellular matrix.

Key Figure, Figure 2.. Dysregulation of macrophage pro-resolution functions.

(A) Following an acute inflammatory response (orange), resolution ensues (blue) leading to a return to homeostasis. (B) In response to an inflammatory trigger, the optimal response (purple) is characterized by an initial increase in macrophage pro-resolution functions followed by a decrease in macrophage pro-resolution functions and the restoration of homeostasis. During fibrotic disease (blue) there is an initial increase in macrophage pro-resolution functions, followed by excessive/prolonged pro-resolution functions. This results in overexuberant repair processes characterized by increased production of macrophage-derived factors that activate fibroblasts and lead to ECM remodeling and fibrosis [91]. An excess of pro-resolution factors is also characteristic of cancer [91]. During SARS-CoV-2 infection (orange), macrophage pro-resolution functions are insufficient, leading to exacerbated inflammation [113-118]. Other conditions including atherosclerosis, neurodegeneration, and autoimmune diseases can also arise due to insufficient resolution (e.g. via lack of efferocytosis) [93]. ECM, extracellular matrix; GFs, growth factors; MMPs, matrix metalloproteinases; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor beta.