Pro‐inflammatory response resulting from sindbis virus infection of human macrophages: Implications for the pathogenesis of viral arthritis

Abstract

Several viruses cause acute and chronic joint inflammation in humans, and among them, the alphaviruses are of special interest due to the increasing number of outbreaks in which they are the etiological factor. Sindbis virus (SinV), a member of the Alphavirus genus, is the most widely distributed of all known arboviruses. Although SinV causes arthritis in humans, the molecular and cellular factors that contribute to the pathogenesis of this disease are almost completely unknown. Despite the crucial role of macrophages in the development of arthritis, these cells have not been recognized as potential targets for viruses causing arthritis. In this study, replication of SinV in human macrophages was demonstrated. The infection promoted macrophage activation, leading to the release of macrophage migration inhibitor factor (MIF) from intracellular stores and inducing the expression and secretion of TNF-alpha, IL-1beta, and IL-6. Production of these cytokines was followed by the expression of matrix metalloproteinases (MMPs) 1 and 3, which could be involved in the articular damage that has been observed in disease induced by SinV. The use of different strategies to block MIF action, including an anti-MIF antibody, the MIF inhibitor ISO-1 and knockout mice for the MIF gene, showed that cytokine secretion and MMP expression during infection were regulated by MIF, suggesting that this cytokine acts in autocrine and paracrine manner upstream in the macrophage activation cascade. Thus, these are remarkable similarities between macrophage responses induced by SinV infection and those observed in rheumatoid arthritis, despite the different etiologies of infectious and autoimmune arthritides.

Seroprevalence of Sindbis virus and associated risk factors in northern Sweden

“…There is growing support for a causal role for infection in triggering stroke, linking infection and inflammation, thrombosis and stroke [27,28]. Furthermore, remarkable similarities have been found between pro-inflammatory macrophage responses induced by SINV infection and those observed in rheumatoid arthritis, despite the different aetiologies of infectious and autoimmune arthritides [29]. Interestingly, the genetic predisposition for SINV infection, HLA-DRB1*01, has also been linked to rheumatoid arthritis and similar genetic predisposing factors may contribute to the development of SINV-induced and autoimmune arthritides resulting in disease with similar features although different aetiologies are involved [3].…”

Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis

“…A number of in vitro studies on the role of MIF in viral infections, including influenza, human cytomegalovirus, and Sindbis virus (42)(43)(44), have shown an increase in the level of MIF following infection. These findings, however, are limited because of the absence of corresponding in vivo studies.…”

Molecular Mechanisms Involved in the Pathogenesis of Alphavirus-Induced Arthritis

“…Additionally, pharmacological depletion of macrophages in mouse models of RRV and CHIKV infection resulted in lesser extent of muscular/articular damage, demonstrating the importance of macrophages for disease progression [33, 37, 73]. The ability of other alphaviruses besides RRV to replicate and persist in macrophages has also been demonstrated [74–76]. Primary human monocytes and macrophages infected with SINV and CHIKV showed a highly productive viral replication [75, 76].…”