Interleukin-17 contributes to Ross River virus-induced arthritis and myositis

Abstract

Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17–producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.

Chikungunya Immunopathology as It Presents in Different Organ Systems

“…IL-17 can promote inflammatory cytokines such as TNF-α and IL-1 [134]. In mice, it has been shown that both CD4 and CD8 T cells remain within joint tissues even after RRV viral clearance [134]. This is similar to clinical CHIKV data, as humans and animals infected with CHIKV show an increased Th17 inflammatory response, marked by an increase in IL-6, IL-17, and IFN-α [133,[136][137][138].…”

“…There are other alphaviruses which cause persistent joint pain, including Ross River virus (RRV), Barmah Forest virus (BFV), Mayaro virus (MAYV), and o'nyoung'nyoung virus (ONNV), which CHIKV is closely genetically related to [134,135]. In RRV, joint pain is associated with increased levels of IL-17 produced by T cells that circulate in host tissues to fend off the virus [134]. IL-17 can promote inflammatory cytokines such as TNF-α and IL-1 [134].…”

“…In RRV, joint pain is associated with increased levels of IL-17 produced by T cells that circulate in host tissues to fend off the virus [134]. IL-17 can promote inflammatory cytokines such as TNF-α and IL-1 [134]. In mice, it has been shown that both CD4 and CD8 T cells remain within joint tissues even after RRV viral clearance [134].…”

Role of MXRA8 in Ross River Virus Disease Pathogenesis

“…Notably, however, IL-17A was observed at higher levels in RRV-infected MXRA8 −/− mice at 3 dpi. IL-17 has recently been shown to contribute to CHIKV and RRV disease ( 31 , 32 ). The upregulation of IL-17A at 3 dpi of RRVD suggests MXRA8 deficiency may alter T cell differentiation of the Th17 axis during the onset of RRVD.…”

Host Immune Responses to Arthritogenic Alphavirus Infection, with Emphasis on Type I IFN Responses

“…In a recent study, IL-17A has been reported to be associated with tissue inf lammation as well as neutrophil infiltration in CHIKV-induced RA [28]. In another recent study on IL-17 in RRV disease, IL-17 has been found to be responsible for RRV-induced arthritis and myositis [52]. IL-17 expression is up-regulated in musculoskeletal tissues and sera of RRV infected mice and humans.…”