Macrophage fate: to kill or not to kill?

Abstract

Macrophages are dynamic innate immune cells that either reside in tissue, serving as sentinels, or recruited as monocytes from bone marrow into inflamed and infected tissue. In response to cues in the tissue microenvironment (TME), macrophages polarize on a continuum toward M1 or M2 with diverse roles in progression and resolution of disease. M1-like macrophages exhibit proinflammatory functions with antimicrobial and anti-tumorigenic activities, while M2-like macrophages have anti-inflammatory functions that generally resolve inflammatory responses and orchestrate a tissue healing process. Given these opposite phenotypes, proper spatiotemporal coordination of macrophage polarization in response to cues within the TME is critical to effectively resolve infectious disease and regulate wound healing. However, if this spatiotemporal coordination becomes disrupted due to persistent infection or dysregulated coagulation, macrophages' inappropriate response to these cues will result in the development of diseases with clinically unfavorable outcomes. Since plasticity and heterogeneity are hallmarks of macrophages, they are attractive targets for therapies to reprogram toward specific phenotypes that could resolve disease and favor clinical prognosis. In this review, we discuss how basic science studies have elucidated macrophage polarization mechanisms in TMEs during infections and inflammation, particularly coagulation. Therefore, understanding the dynamics of macrophage polarization within TMEs in diseases is important in further development of targeted therapies.

Keywords: M1; M1/M2; M2; coagulation; innate immunity; macrophage polarization; macrophages; tissue microenvironment.

Fig 1

Tissue microenvironment signals induce M1 and M2 macrophage polarization on a spectrum. (Step 1) In the initial response to infection and/or damage, tissue-resident macrophages (TRMɸs) serve as sentinels by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to stimulate CCL2 for monocyte recruitment. (Step 2) Monocytes extravasate into the tissue where (Step 3) Macrophage-colony stimulating factor (M-CSF) differentiates monocytes into naive (M0) monocyte-derived macrophages (MDMɸs). (Step 4) Factors including PAMPs, DAMPs, and cytokines produced by T_H1 and T_H2 cells then induce M1 and M2 polarization on a spectrum. IFN-γ, LPS, and GM-CSF induce M1-like polarization leading to a signaling cascade that enables transcription factors STAT1, activator protein-1 (AP-1), NFκB, IRF3, and IRF5 to activate proinflammatory genes. Cytokines and chemokines produced by M1s activate CD8⁺ cytotoxic T cells (T_c), T_H1, natural killer (NK) cells, and neutrophils (PMN). Virus-infected macrophages can also present viral antigens on their major histocompatibility complex-I (MHC-I) to T_C cells, resulting in granzyme release that induces apoptosis. Macrophages infected with bacteria or fungi can present their antigen on MHC-II to T_H1 cells resulting in IFN-γ secretion. IFN-γ promotes phagocytosis and upregulates iNOS to produce NOs degrading the pathogen. IL-4, IL-13, immune complexes, and glucocorticoids induce M2-like polarization. For M2-like polarization, signaling cascades activate transcription factors IRF4, STAT3, STAT6, PPARɑ, and CCAAT/enhancer-binding protein beta (C/EBPβ) to induce anti-inflammatory genes. Cytokines and chemokines produced by M2s dampen M1s, NKs, and PMNs inflammatory response. Furthermore, these factors activate T_H2 and regulatory T cells (T_reg) to secrete cytokines to suppress phagocytosis, ultimately resulting in pathogen survival and persistence. (Step 5) At the same time, endothelial cells produce IL-6, which stimulates hepatocytes to produce Fg and infiltrate into the tissue to form fibrin clots by proteolytic activity of thrombin for tissue repair.

Fig 2

Pathogens can modulate macrophage polarization leading to microbial clearance or survival. Bacteria, viruses, and fungi species can promote macrophages toward (A) M1 or (B) M2 polarization on a continuum affecting the outcome of infection.

Fig 3

Vascular and tissue injury activates the coagulation cascade leading to fibrin clot formation. (A) Vascular damage activates the intrinsic pathway of the coagulation cascade by proteolytic cleavage of FXII, FXI, and FIX. Activation of FVIII produces FVIIIa to form a complex with FIXa (FIXa:FVIIIa) to subsequently cleave FX into FXa. (B) Tissue injury initiates the extrinsic pathway of the coagulation cascade by activating FIII (Tissue Factor) and FVII to generate the FIIIa:FVIIa complex. The FIIIa:FVIIa complex cleaves FX to produce FXa. (C) Both FXa and FVa activate FII (prothrombin) into FIIa (thrombin). Thrombin proteolytically cleaves soluble Fg fibrinopeptides to form fibrin fibers. FXIIIa crosslinks fibrin fibers to stabilize fibrin clots. (D) For fibrinolysis to occur, urokinase- (uPA) and tissue-plasminogen activator (tPA) activate plasminogen (PG) into plasmin to degrade fibrin clots generating fibrin degradation products. To halt the fibrinolytic process, uPA and tPA are inhibited by plasminogen activator inhibitor-I (PAI-I).