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.
Highlights
Macrophage involvement in viral infections and antiviral states is common
After perception by the corresponding receptors, the canonical signaling pathway mediated by type I and type III IFNs leads to the activation and dimerization of STAT1 and STAT2, which further recruits IFN-regulatory factor (IRF)-9 to form an IFN-stimulated gene factor (ISGF)-3 complex
Much is still unknown about the mechanisms that regulate type I IFNs either in canonical antiviral stimulation or switching to strengthen M1 or M2 statuses [28,29,30,98]; macrophage polarization progression mediated by the net result of these IFNs and crosstalk with other mediators is likely critical in determining the outcome of monocytotropic viral infections
Summary
Origin and retention of macrophages Macrophages (MΦs), together with blood monocytes (MOs) and dendritic cells (DCs), comprise a mononuclear cell lineage that originates from common myeloid progenitors. In addition to boosting antiviral responses through induction of IFNstimulated genes (IFNs) and pro-inflammatory cytokines (i.e., for M1-like polarization), IFN-α/-β (type I IFNs) and IFN-λs (type III IFNs) potently stimulate the production of IL-10 and other immunosuppressive responses (M2-like) during persistent viral infection (See Section 3 for detail) [27,28,29,30,31] Because of their diverse distribution in the body and the critical role of monocytic cells in immune regulation, multiple viruses have evolved to infect and replicate in both differentiated MΦs and their precursor MOs (Table 1) [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. We will discuss this topic primarily by using examples of respiratory viral infections in humans and animals (Table 1)
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