Role of macrophages in the onset, maintenance, or control of arthritis caused by alphaviruses

Abstract

Arthritogenic alphaviruses are mosquito-borne viruses that cause a debilitating rheumatic disease characterized by fever, headache, rash, myalgia, and polyarthralgia with the potential to evolve into a severe and very prolonged illness. Although these viruses have been geographically restricted by vector hosts and reservoirs, recent epidemics have revealed the risks of their spread worldwide. In this review, we aim to discuss the protective and pathological roles of macrophages during the development of arthritis caused by alphaviruses. The progression to the chronic phase of the disease is related to the extension of viral replication and the maintenance of articular inflammation, in which the cellular infiltrate is predominantly composed of macrophages. We explore the possible implications of macrophage polarization to M1/M2 activation phenotypes, drawing a parallel between alphavirus arthritis and rheumatoid arthritis (RA), a chronic inflammatory disease that also affects articular tissues. In RA, it is well established that M1 macrophages contribute to tissue damage and inflammation, while M2 macrophages have a role in cartilage repair, so modulating the M1/M2 macrophage ratio is being considered as a strategy in the treatment of this disease. In the case of alphavirus-induced arthritis, the picture is more complex, as proinflammatory factors derived from M1 macrophages contribute to the antiviral response but cause tissue damage, while M2 macrophages may contribute to tissue repair but impair viral clearance.

Keywords: Alphaviruses; antiviral response; arthritis; inflammation; macrophage; tissue damage and repair.

Figure 1.

Geographical distribution of arthritogenic alphaviruses with the years of the main outbreaks (a) until 2000 and (b) between 2001 and 2020. Figure adapted from Zaid A et al. (c) Schematic illustration of the main clinical manifestations of arthritogenic alphavirus infections. Source: Figure created using BioRender.com. BFV: Barmah Forest virus; CHIKV: Chikungunya virus; MAYV: Mayaro virus; ONNV: O’nyong-nyong virus; RRV: Ross River virus; SINV: Sindbis virus.

Figure 2.

Profile of cytokine production during the (a) early and (b) late stages of alphavirus-induced arthritis, with the respective virus for which each cytokine was detected. Proinflammatory cytokines (TNF, CCL2, IL-8, IL-6, and IFN-γ) are represented on the left of each panel, and anti-inflammatory cytokines (IL-4, IL-13, and IL-10) and the M2 macrophage receptor CXCR1 are represented on the right of each panel. The balance scale illustrates the contribution of the macrophage phenotype in each disease stage. Source: Figure created using BioRender.com. MAYV: Mayaro virus; CHIKV: Chikungunya virus; RRV: Ross River virus.