Macrophage Polarization in Virus-Host Interactions

Abstract

Macrophage involvement in viral infections and antiviral states is common. However, this involvement has not been well-studied in the paradigm of macrophage polarization, which typically has been categorized by the dichotomy of classical (M1) and alternative (M2) statuses. Recent studies have revealed the complexity of macrophage polarization in response to various cellular mediators and exogenous stimuli by adopting a multipolar view to revisit the differential process of macrophages, especially those re-polarized during viral infections. Here, through examination of viral infections targeting macrophages/monocytic cells, we focus on the direct involvement of macrophage polarization during viral infections. Type I and type III interferons (IFNs) are critical in regulation of viral pathogenesis and host antiviral infection; thus, we propose to incorporate IFN-mediated antiviral states into the framework of macrophage polarization. This view is supported by the multifunctional properties of type I IFNs, which potentially elicit and regulate both M1- and M2-polarization in addition to inducing the antiviral state, and by the discoveries of viral mechanisms to adapt and modulate macrophage polarization. Indeed, several recent studies have demonstrated effective prevention of viral diseases through manipulation of macrophage immune statuses.

Keywords: Antiviral state; Interferon; Macrophage polarization; Viral infection; Virus-host interaction.

Figure 1

Incorporation of the antiviral state into a multilayer scheme of macrophage polarization. The top panel illustrates recent findings about the origin and self-renewal property of tissue macrophages. In contrast to the dichotomy system for addressing macrophage polarization that classifies macrophages either as classic (M1) or alternative (M2) activation statuses, a multipolar view has been proposed to revise macrophage polarization based on a much broader functional repertoire for macrophages mediated by various mediators/stimuli grouped in different layers [1,6]. Antiviral state (MaV), which is a cell-autonomous status to restrict virus infection and replication in response to viral infection or IFN stimulation, has not been well integrated into the paradigm of macrophage activation. In line with our previous work to study MaV in the framework of macrophage activation [70], here we elaborate the potential diversity of MaV states corresponding to the multifunctional properties of type I and type III IFNs as shown in Figure 2. CMP: Common Myeloid Progenitor; CXCL: Chemokine C-X-C Motif Ligand; DC: Dendritic Cells; (G)M-CSF: (Granulocyte-) Macrophage Colony-Stimulating Factor; MO: Monocyte; MΦ: Macrophage; NLR: NOD-Like Receptors; PPARγ: Peroxisome Proliferator-Activated Receptor gamma; PRR: Pathogen Recognition Receptor; RA: Retinoic Acid; RLR: RIG-Like Receptor; TLR: Toll-Like Receptor; VitD3: Vitamin D3. Modified from Martinez and Gordon [6].

Figure 2

Ramification of IFN signaling pathways leading to immunostimulatory and immunosuppressive regulation of macrophage polarization. Viral infection of tissue-resident macrophages or nearby cells leads to production of type I and type III IFNs, which are perceived by distinct membrane-bound receptor complexes but stimulate similar signaling pathways in the infected or other proximal macrophages. In addition to the canonical signaling pathway through STAT1/STAT2/IRF9 (also known as the ISGF3) binding to IFN-stimulated response elements (ISREs) in gene promoters, leading to induction of a large number of IFN-stimulated genes (ISGs) and pro-inflammatory responses, both types of IFNs, in particular manifested using type I IFNs, also signal through STAT1 homodimers, which are more commonly associated with the IFNγ-mediated signaling pathway for classical activation (M1) macrophages. Other STAT heterodimers and homodimers (including STAT3-6) may also be activated but lead to production of anti-inflammatory and immunosuppressive IL-10 and IL-1Ra. Other STAT-independent signaling pathways including MAPK- and PI3K-pathways also may be activated, thereby exerting diverse effects in macrophages as well as other immune cells (such effects on T cell, in particular Treg cell ratio), which critically regulate the outcomes of virus-host interaction through, at least in part, the modulation of macrophage polarization [30,31].