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

Abstract

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 g 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.

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

“…A study by Patole et al 25 investigated the effect of polyI:C, an IFNab-inducing component resembling viral dsRNA, on kidney cells. They found that mesangial cells expressed the dsRNA receptor toll-like receptor-3 and responded specifically to polyI:C treatment by producing chemokines and cytokines.…”

Toll-Like Receptor 2 Agonists Exacerbate Accelerated Nephrotoxic Nephritis

“…In models of chronic glomerular disease, viral doublestranded RNA, a known TLR3 ligand, and bacterial DNA, a TLR9 ligand, have been shown to aggravate lupus nephritis (37,38). Bacterial DNA also has been shown to aggravate horse apoferritin-induced glomerulonephritis.…”

FcγRIIIa-Syk Co-signal Modulates CD4+ T-cell Response and Up-regulates Toll-like Receptor (TLR) Expression

“…10 and Table 1). TLR3 showed the most increase and is shown to aggravate lupus nephritis (51). To examine the presence of TLR proteins and their association with Fc␥RIIIa in CD4 ϩ T-cells, we stained P116 cells after co-stimulation with ICsϩC5b-9.…”