Amelioration of alphavirus-induced arthritis and myositis in a mouse model by treatment with bindarit, an inhibitor of monocyte chemotactic proteins.
OBJECTIVE
Alphaviruses such as chikungunya virus, Sindbis virus, o'nyong-nyong virus, Mayaro virus, and Ross River virus (RRV), are commonly associated with arthralgias and overt arthritides worldwide. Understanding the processes by which arthritogenic viruses cause disease is a prerequisite in the quest for better treatments. In this regard, we have recently established that monocyte/macrophages are mediators of alphavirus-induced arthritis in mice. We hypothesized that chemokines associated with monocyte/macrophage recruitment may play an important role in disease. The aim of the present investigations was to determine whether bindarit, an inhibitor of monocyte chemotactic protein (MCP) synthesis, could ameliorate alphavirus-induced rheumatic disease in mice.


METHODS
Using our recently developed mouse model of RRV-induced arthritis, which has many characteristics of RRV disease (RRVD) in humans, the effects of bindarit treatment on RRVD in mice were determined via histologic analyses, immunohistochemistry, flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and electrophoretic mobility shift assay.


RESULTS
Bindarit-treated RRV-infected mice developed mild disease and had substantially reduced tissue destruction and inflammatory cell recruitment as compared with untreated RRV-infected mice. The virus load in the tissues was not affected by bindarit treatment. Bindarit exhibited its activity by down-regulating MCPs, which in turn led to inhibition of cell infiltration and lower production of NF-kappaB and tumor necrosis factor alpha, which are involved in mediating tissue damage.


CONCLUSIONS
Our data support the use of inhibitors of MCP production in the treatment of arthritogenic alphavirus syndromes and suggest that bindarit may be useful in treating RRVD and other alphavirus-induced arthritides in humans.
Rulli
Nestor E
NE
Faculty of Applied Science, University of Canberra, Canberra, ACT, Australia.
Guglielmotti
Angelo
A
Mangano
Giorgina
G
Rolph
Michael S
MS
Apicella
Claudia
C
Zaid
Ali
A
Suhrbier
Andreas
A
Mahalingam
Suresh
S
D000524:Alphavirus / Q000276:immunology; D018354:Alphavirus Infections / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018945:Monocyte Chemoattractant Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009220:Myositis / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D011422:Propionates / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism
D018501:Antirheumatic Agents; D007191:Indazoles; D018945:Monocyte Chemoattractant Proteins; D011422:Propionates; D012333:RNA, Messenger; C079489:bindarit