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Toll-Like Receptor-7 Modulates Immune Complex Glomerulonephritis

Nephrological Center, Medical Policlinic, University of Munich, Munich, Germany

Address correspondence to: Dr. Hans-Joachim Anders, Medizinische Poliklinik, Klinikum der Universität–Innenstadt, Pettenkoferstrasse 8a, 80336 Munich, Germany. Phone: +49-89-2180-75846; Fax: +49-89-2180-75860; hjanders{at}med.uni-muenchen.de

Received for publication July 13, 2005. Accepted for publication September 28, 2005.

Viral infections may trigger immune complex glomerulonephritis via Toll-like receptors (TLR), as certain TLR trigger immunity upon recognition of viral nucleic acids. On the basis of previous findings regarding viral double-stranded RNA and TLR3 in experimental lupus erythematosus, a similar role for TLR7 that recognizes viral single-stranded RNA was hypothesized. Immunostaining of kidney sections of nephritic MRL^lpr/lpr mice revealed TLR7 expression in infiltrating ER-HR3–positive macrophages and few CD11c-positive dendritic cells but not in glomerular mesangial cells as observed for TLR3. This finding was consistent with the distribution pattern of intravenously injected single-stranded RNA in nephritic MRL^lpr/lpr mice. TLR7 ligation activated monocytes and dendritic cells, both isolated from MRL^lpr/lpr mice, to secrete IFN-, IL-12p70, IL-6, and CCL2. In vivo, a single injection of the TLR7 ligand imiquimod increased serum levels of IL-12p70, IFN-, and IL-6. A course of 25 µg of imiquimod given every other day from week 16 to 18 of age aggravated lupus nephritis in MRL^lpr/lpr mice. This was associated with increased glomerular immune complex deposits as well as interstitial expression of CCL2 in imiquimod-treated MRL^lpr/lpr mice. Different types of viral nucleic acids seem to modulate systemic autoimmunity through specific interactions with their respective TLR. Different TLR expression profiles on immune cell subsets and nonimmune parenchymal cell types determine the molecular mechanisms involved in viral infection–associated exacerbation of lupus nephritis and possibly other types of immune complex glomerulonephritis.

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