Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus.
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.
Lidbury
Brett A
BA
Virus and Inflammation Research Group, Faculty of Sciences, University of Canberra, Australia.
Rulli
Nestor E
NE
Suhrbier
Andreas
A
Smith
Paul N
PN
McColl
Shaun R
SR
Cunningham
Anthony L
AL
Tarkowski
Andrej
A
van Rooijen
Nico
N
Fraser
Robert J
RJ
Mahalingam
Suresh
S
D000328:Adult; D018354:Alphavirus Infections / Q000150:complications* / Q000276:immunology; D000818:Animals; D000842:Ankle / Q000473:pathology / Q000821:virology; D001168:Arthritis / Q000276:immunology* / Q000473:pathology; D001835:Body Weight; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D047589:Leukocyte Reduction Procedures; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008875:Middle Aged; D009132:Muscles / Q000473:pathology / Q000821:virology; D009220:Myositis / Q000276:immunology* / Q000473:pathology; D012398:Ross River virus / Q000276:immunology*; D012720:Severity of Illness Index; D013582:Synovial Fluid / Q000276:immunology
D016207:Cytokines