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Viral Double-Stranded RNA Aggravates Lupus Nephritis through Toll-Like Receptor 3 on Glomerular Mesangial Cells and Antigen-Presenting Cells

Prashant S. Patole^*, Hermann-Josef Gröne, Stephan Segerer^*, Raluca Ciubar^*, Emilia Belemezova^*, Anna Henger^*, Matthias Kretzler^*, Detlef Schlöndorff^* and Hans-Joachim Anders^*

^* Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University, Munich; and Division of Molecular and Cellular Pathology, German Cancer Research Center, Heidelberg, Germany

Address correspondence to: Dr. Hans-Joachim Anders, Medizinische Poliklinik der LMU, Pettenkoferstrasse 8a, 80336 Munich, Germany. Phone: +49-89-21807846; Fax: +49-89-218075860; E-mail: hjanders{at}med.uni-muenchen.de

Received for publication October 4, 2004. Accepted for publication January 19, 2005.

How viral infections trigger autoimmunity is poorly understood. A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE). Immunostaining of nephritic kidney sections of autoimmune MRL^lpr/lpr mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells. TLR3-positive cultured mesangial cells that were exposed to synthetic polyinosinic-cytidylic acid (pI:C) RNA in vitro produced CCL2 and IL-6. pI:C RNA activated macrophages and dendritic cells, both isolated from MRL^lpr/lpr mice, to secrete multiple proinflammatory factors. In vivo, a single injection of pI:C RNA increased serum IL-12p70, IL-6, and IFN- levels. A course of 50 µg of pI:C RNA given every other day from weeks 16 to 18 of age aggravated lupus nephritis in pI:C-treated MRL^lpr/lpr mice. Serum DNA autoantibody levels were unaltered upon systemic exposure to pI:C RNA in MRL^lpr/lpr mice, as pI:C RNA, in contrast to CpG-DNA, failed to induce B cell activation. It therefore was concluded that viral dsRNA triggers disease activity of lupus nephritis by mechanisms that are different from those of bacterial DNA. In contrast to CpG-DNA/TLR9 interaction, pI:C RNA/TLR3-mediated disease activity is B cell independent, but activated intrinsic renal cells, e.g., glomerular mesangial cells, to produce cytokines and chemokines, factors that can aggravate autoimmune tissue injury, e.g., lupus nephritis.

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