Elsevier

Immunobiology

Volume 223, Issue 1, January 2018, Pages 101-111
Immunobiology

Review
The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2

https://doi.org/10.1016/j.imbio.2017.10.005Get rights and content

Highlights

  • Exposure of monocytes to inflammatory or anti-inflammatory conditions induces differentiation to M1 or M2 subsets.

  • Exposure of monocytes to inflammatory or anti-inflammatory conditions leads to phenotype switch between macrophage subsets.

  • IRFs play a key role in c development of monocytes, their differentiation to macrophages.

  • Impact of IRFs on macrophage phenotype plasticity and heterogeneity is complex.

  • IRFs involves activating and repressive function in triggering transcription of target genes.

Abstract

The mononuclear phagocytes control the body homeostasis through the involvement in resolving tissue injury and further wound healing. Indeed, local tissue microenvironmental changes can significantly influence the functional behavior of monocytes and macrophages. Such microenvironmental changes for example occur in an atherosclerotic plaque during all progression stages. In response to exogenous stimuli, macrophages show a great phenotypic plasticity and heterogeneity. Exposure of monocytes to inflammatory or anti-inflammatory conditions also induces predominant differentiation to proinflammatory (M1) or anti-inflammatory (M2) macrophage subsets and phenotype switch between macrophage subsets. The phenotype transition is accompanied with great changes in the macrophage transcriptome and regulatory networks. Interferon-regulatory factors (IRFs) play a key role in hematopoietic development of monocytes, their differentiation to macrophages, and regulating macrophage maturation, phenotypic polarization, phenotypic switch, and function. Of 9 IRFs, at least 3 (IRF-1, IRF-5, and IRF-8) are involved in the commitment of proinflammatory M1 whereas IRF-3 and IRF-4 control M2 polarization. The role of IRF-2 is context-dependent. The IRF impact on macrophage phenotype plasticity and heterogeneity is complex and involves activating and repressive function in triggering transcription of target genes.

Graphical abstract

Exposure of monocytes to inflammatory or anti-inflammatory conditions also induces predominant differentiation to proinflammatory (M1) or anti-inflammatory (M2) macrophage subsets and phenotype switch between macrophage subsets (Figure). This review characterizes the roles of interferon-regulatory factors in the polarization of non-activated macrophages (M0) to M1 and M2 macrophages.

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Introduction

In homeostasis, monocytes circulate in the blood, bone marrow, and spleen (Auffray et al., 2009). The function of monocytes in homeostatic conditions is unclear but these cells likely to be involved in the removal of dead cells and toxic compounds and renewal of ‘resident’ macrophages and dendritic cells (DCs) (Geissmann et al., 2008). In inflammation, monocytes in response to proinflammatory stimuli move to inflamed sites and lymphoid tissues. Monocytes neutralize pathogens and toxic molecules, engulf dead, damaged, and exogenous cells, secrete cytokines and differentiate to macrophages and DCs (Woollard and Geissmann, 2010).

In atherosclerosis, a chronic inflammatory vascular disease, monocytes infiltrate intimal and subintimal regions of the arterial wall (Imhof and Aurrand-Lions, 2004). Interestingly, monocytes preferentially transmigrate through the endothelium in so-called athero-prone vascular regions located, for example, in arterial branches and characterized by disturbed/unstable bloodflow and local proinflammatory microenvironment (Davies et al., 2013).

Infiltrated monocytes differentiate to macrophages, which take up modified lipoproteins such as oxidized low density lipoproteins and convert to foam cells to form early intimal lesions defined as fatty streaks (Chistiakov et al., 2016).

In mice, there are two principal monocyte subsets. Circulating Gr1+/Ly6ChighCCR2+CX3CR1low cells are usually referred to as ‘inflammatory monocytes’ since they differentiate to inflammatory macrophages and DCs. Another subset (Gr1/Ly6ClowCCR2 CX3CR1high) represents ‘patrol monocytes’ that scan the endothelium of small vessels (Geissmann et al., 2003). In Apolipoprotein (Apo)E-deficient mice, Gr1+/Ly6Chigh monocytes were observed to attach to the endothelium, infiltrate plaques and transform to atherogenic M1 macrophages (Swirski et al., 2007). Gr1/Ly6Clow monocytes contribute to the formation of alternatively activated M2 macrophages (Tacke et al., 2007). M1 macrophages release inflammatory cytokines and proteases and perform phagocytosis. M2 macrophages are involved in phagocytosis, tissue repair and remodeling, and release chemokines and anti-inflammatory cytokines. Regarding foam cell formation, both M1 and M2 can contribute to their generation, with a putative preferential role of M2 because this subset up-regulates expression of scavenger receptors (SR) SR-A1 and CD36 while SR expression is reduced in M1 (Oh et al., 2012).

Proinflammatory M1 macrophages can be induced by proinflammatory stimuli such as bacterial products (lipopolysaccharides (LPS)) or cytokines like interferon-γ. These macrophages propagate and support the inflammatory reaction through secretion of inflammatory mediators (tumor necrosis factor-α (TNF-α), IL (interleukin)-1β, IL-6, IL-8, IL-12). However, prolonged activity of M1 macrophage eventually damages tissue. By contrast, M2 cells, which can be induced by IL-4/IL-13 and IL-10, liberate anti-inflammatory cytokines (transforming growth factor-β (TGF-β), IL-10) to resolve the immune response (Wolfs et al., 2011). Indeed, well-controlled M1/M2 balance is important to avoid pathology or acute reactions.

This control can be effectively achieved by macrophage phenotypic plasticity. In tissue injury, M1 macrophages come to the wounded place, kill pathogens, neutralize toxins, and clear dead cells and cell debris. M2 macrophages are then recruited to repair tissue and heal the wound (Lee et al., 2011). To avoid the mobilization of new monocytes/macrophages, M1 macrophages can switch the phenotype to M2 depending on the local microenvironment (Huen and Cantley, 2015). Indeed, in the model of ischemic kidney injury, a heterogeneity of macrophage phenotypes was observed (Lee et al., 2011). Similarly, a variety of macrophage phenotypes was detected in the atherosclerotic plaque (reviewed recently by Chistiakov et al., 2015a, Rojas et al., 2015, Tabas and Bornfeldt, 2016).

The M1/M2 balance is dynamic and controlled by activity of intracellular signaling mediators activated by exogenous stimuli. A prevalence of nuclear factor-kB (NF-kB) and signal transducer and activator of transcription-1 (STAT-1) activity stimulates M1 polarization while predominance of STAT-3 and STAT-6-dependent signaling activated by IL-4, IL-10 or IL-13 induces M2 macrophage polarization (Wang et al., 2014). An existence of a new M3 ‘switch’ phenotype, which responds to proinflammatory signals with reprogramming towards the M2 phenotype or, contrarily, to anti-inflammatory stimuli with reprogramming towards the M1 phenotype, was hypothesized (Malyshev and Malyshev, 2015). Indeed, the presence of M3 updates the existing concept of macrophage plasticity. However, direct proofs for the occurrence of M3 should be mined.

Section snippets

Macrophage differentiation factors in lesions

Macrophage and granulocyte-macrophage stimulating factors (M-CSF and GM-CSF) are principal hemapoietic growth factors that control differentiation of monocytes to macrophages. In the presence of GM-CSF, bone marrow cells differentiate to macrophages with antigen-presenting abilities, which in turn can give rise to DCs (in the presence of IL-4) (Hiasa et al., 2009). M-CSF drives transformation of bone marrow cells to macrophages with advanced phagocytic properties (Hamilton, 2008). Macrophages

A family of interferon-regulatory factors

Interferon-regulatory factors (IRFs) are crucially involved in differentiation and polarization of macrophages. These factors were found due to their ability to bind to the virus-responsive elements in the promoter region of type I IFN genes. All IRFs are able to activate expression of IFN-α whereas IRF-3 in cooperation with NF-kB prime transcription of the IFN-β gene (Savitsky et al., 2010). Development and studying of IRF-deficient mice revealed new roles of IRFs in immunity, cell growth, and

IRF-3: a role in macrophage differentiation and M2 polarization

The human IRF-3 gene is located on chromosome 19q13 and could be alternatively spliced that results in the formation of 6 protein isoforms with varying length. The full-length isoform is 427 a.a-long (Nguyen et al., 1997). In addition to the DNA-binding domain and IAD1 domain, IRF-3 molecule contains the regulatory domain that flanks IAD1, the nuclear localization site, and two repression domains of which one is C-terminal (Fig. 1) (Ferrante and Leibovich, 2012). The nuclear localization site

IRF-4: a role in M2 polarization

Human IRF-4 is encoded by a corresponding gene located on chromosome 6p25. Two alternative transcripts transcribed from this gene encodes the same protein of 450 residues in length. IRF-4 displays a considerable sequence similarity with IRF-1 and IRF-2 (Eisenbeis et al., 1995). Along with the conserved DNA-binding domain and IAD1-domain, IRF-4 has regulatory domains and a repression domain sandwiched between the IAD1 and C-terminal regulatory domain (Fig. 1). This protein acts as a

IRF-5: a role in M1 polarization

Human IRF5 gene resides on chromosome 7q32 and can be alternatively transcribed generating four protein isoforms the longest of which is 504 a.a.-long. IRF5 is ubiquitously expressed (Takaoka et al., 2005). This factor contains the DNA-binding domain, IAD1-domain flanked by regulatory domains, and C-terminal repression domain (Fig. 1).

IRF-5 is induced in response to stimulation by several proinflammatory signaling mechanisms scheduled from TLRs, RIG-1-like receptors, and other PRRs (Ryzhakov et

The role of other IRFs in macrophage polarization

Other factors from the IRF family contribute to phenotypic polarization of macrophage although their impact is less evident than a role of factors mentioned above.

Conclusion

In Fig. 3, we have depicted key TLR-mediated effects in TLR-dependent proinflammatory activation of macrophages.

The findings presented above suggest for a non-redundant role of the IRF family of transcription regulators in monocyte-macrophage development, maturation, and differentiation. However, the molecular mechanisms that drive differentiation into the Ly6Chigh inflammatory and Ly6Clow monocyte subsets are yet to be completely elucidated to understand, for example, whether IRF-8 can be

Conflict of interest

The authors report no conflict of interest.

Acknowledgement

We wish to thank the Russian Science Foundation (Grant #14-15-00112) for support of our work.

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