Arthritogenic properties of double-stranded (viral) RNA.
Viral infections often lead to arthralgias and overt arthritic states. The inflammatogenic compound of the viruses giving rise to such an outcome has to date not been identified. Because expression of dsRNA is a common feature of all viruses, we decided to analyze whether this property leads to the induction of arthritis. Histological signs of arthritis were evident already on day 3 following intra-articular administration of dsRNA. Arthritis was characterized by infiltration of macrophages into synovial tissue. It was not dependent on acquired immune responses because SCID mice also raised joint inflammation. NF-kappa B was activated upon in vitro exposure to dsRNA, indicating its role in the induction/progression of arthritis. Importantly, we found that dsRNA arthritis was triggered through IL-1R signaling because mice being deficient for this molecule were unable to develop joint inflammation. Although dsRNA is typically recognized by Toll-like receptor 3, Toll-like receptor 3 knockout mice developed arthritis, indicating that some other receptors are instrumental in the inducing of inflammation. Our results from in vitro experiments indicate that proinflammatory cytokines and chemokines stimulating monocyte influx were readily triggered in response to stimulation with dsRNA. These findings demonstrate that viral dsRNA is clearly arthritogenic. Importantly, macrophages and their products play an important role in the development of arthritis triggered by dsRNA.
Zare
Fariba
F
Department of Rheumatology and Inflammation Research, University of Göteborg, Gothenburg, Sweden. fariba.zare@rheuma.gu.se
Bokarewa
Maria
M
Nenonen
Nancy
N
Bergström
Thomas
T
Alexopoulou
Lena
L
Flavell
Richard A
RA
Tarkowski
Andrej
A
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000821:virology*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007270:Injections, Intra-Articular; D015850:Interleukin-6 / Q000097:blood; D007970:Leukopenia / Q000139:chemically induced / Q000276:immunology; D008264:Macrophages / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000502:physiology; D011070:Poly I-C / Q000008:administration & dosage / Q000633:toxicity; D012330:RNA, Double-Stranded / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*; D012367:RNA, Viral / Q000008:administration & dosage / Q000138:chemical synthesis / Q000633:toxicity*; D011956:Receptors, Cell Surface / Q000502:physiology; D012401:Rotavirus / Q000737:chemistry; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors
D018925:Chemokines; D016207:Cytokines; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D011070:Poly I-C