Macrophage‐Derived Proinflammatory Factors Contribute to the Development of Arthritis and Myositis after Infection with an Arthrogenic Alphavirus

Abstract

Alphaviruses, such as chikungunya virus and Ross River virus (RRV), are associated with outbreaks of infectious rheumatic disease in humans worldwide. Using an established mouse model of disease that mimics RRV disease in humans, we showed that macrophage-derived factors are critical in the development of striated muscle and joint tissue damage. Histologic analyses of muscle and ankle joint tissues demonstrated a substantial reduction in inflammatory infiltrates in infected mice depleted of macrophages (i.e., "macrophage-depleted mice"). Levels of the proinflammatory factors tumor necrosis factor-alpha, interferon-gamma, and macrophage chemoattractant protein-1 were also dramatically reduced in tissue samples obtained from infected macrophage-depleted mice, compared with samples obtained from infected mice without macrophage depletion. These factors were also detected in the synovial fluid of patients with RRV-induced polyarthritis. Neutralization of these factors reduced the severity of disease in mice, whereas blocking nuclear factor kappaB by treatment with sulfasalazine ameliorated RRV inflammatory disease and tissue damage. To our knowledge, these findings are the first to demonstrate that macrophage-derived products play important roles in the development of arthritis and myositis triggered by alphavirus infection.

Arthrogenic Alphaviruses and Inflammatory Myopathies

“…The levels of complement factor C3a, MCP-1, TNF-, IFN- and RNI were all elevated in RRV patients (Lidbury et al, 2008;Morrison et al, 2007). Furthermore, cells obtained from synovial fluid have been found to be mononuclear in nature being mainly monocytes and activated macrophages (Clarris et al, 1975;Fraser et al, 1981).…”

“…A small animal model of RRV-disease has been developed in 20-24 day old C57BL/6 mice (Lidbury et al, 2008;Morrison et al, 2007;Morrison et al, 2006), subcutaneously infected with RRV. The infection progresses with virus titre peaking in the first 24-48 hours postinfection (p.i.…”

“…It has been shown that infiltrating macrophages are a key mediator of muscle tissue destruction by mechanisms which involve the production of soluble factors such as macrophage inflammatory protein (MIP)-1, IFN-, interleukin (IL)-1, reactive nitogen intermediates (RNI), tumour necrosis factor (TNF)-, and monocyte chemoattractant protein (MCP)-1 (Lidbury et al, 2008). In the macaque model of CHIKV infection, an up-regulation of IFN-/, IFN-, MCPs, IL-6 and TNF- was detected, all synonymous with a strong, macrophage-induced inflammatory response (Labadie et al, 2010).…”

“…In the macaque model of CHIKV infection, an up-regulation of IFN-/, IFN-, MCPs, IL-6 and TNF- was detected, all synonymous with a strong, macrophage-induced inflammatory response (Labadie et al, 2010). IL-1, RNI and TNF- are factors known to trigger apoptosis (Bhaumik & Khar, 1998;Griffin & Hardwick, 1997;Roulston et al, 1999) while MCP-1 and MIP-1 are involved in amplifying the inflammatory response (Carr et al, 1994;Lidbury et al, 2008;Ren et al, 2010;Wolpe et al, 1988). Macrophages have also been implicated as a cellular reservoir for alphavirus persistence and therefore a contributing factor in the development of chronic disease symptoms.…”

“…Animal models have been used to determine the role of various cytokines and chemokines in the development of alphaviral-induced myopathies. Studies have shown that IFN-, TNF-, IL-1, IL-6, macrophage inflammatory protein (MIP)-1, MCP-1, MCP-2, and MCP-3 are up-regulated in response to RRV infection (Lidbury et al, 2008;Rulli et al, 2009). The high levels of these factors in diseased tissues implicate their role in RRV-induced myositis (Lidbury et al, 2008;Rulli et al, 2009).…”