Inhibition of toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus

• Published in: Journal of the American Society of Nephrology 2007-06, Vol.18 (6), p.1721-1731
• Main Authors: PAWAR, Rahul D, RAMANJANEYULU, Allam, KULKARNI, Onkar P, LECH, Maciej, SEGERER, Stephan, ANDERS, Hans-Joachim
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Aminoquinolines - pharmacology; Animals; Autoantibodies - blood; Biological and medical sciences; Female; Genetic Therapy - methods; Glomerulonephritis; Interleukin-6 - blood; Interleukin-6 - secretion; Kidney - immunology; Lupus Nephritis - immunology; Lupus Nephritis - therapy; Medical sciences; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Mice; Mice, Inbred MRL lpr; Monocytes - drug effects; Monocytes - metabolism; Monocytes - secretion; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oligodeoxyribonucleotides - pharmacology; Respiratory Distress Syndrome, Adult - immunology; Respiratory Distress Syndrome, Adult - therapy; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal Transduction - drug effects; Signal Transduction - immunology; Spleen - cytology; Toll-Like Receptor 7 - antagonists & inhibitors; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - antagonists & inhibitors; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - secretion
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2006101162

Small nuclear RNA and associated lupus autoantigens activate B cells and dendritic cells via Toll-like receptor-7 (TLR-7); therefore, TLR-7 may represent a potential therapeutic target in lupus. MRL lpr mice were administered an injection of either saline or synthetic oligodeoxynucleotides with immunoregulatory sequences (IRS) that specifically block signaling via TLR-7 (IRS 661) or via TLR-7 and TLR-9 (IRS 954, which uses a active sequence from IRS 661 along with a TLR-9 inhibitory sequence) from weeks 11 to 24 of age. IRS 661 and IRS 954 both significantly reduced the weight of spleen and lymph nodes as well as serum levels of TNF as compared with saline-treated MRL lpr mice. Only IRS 661 but not IRS 954 significantly reduced serum levels of IL-12p40, anti-dsDNA IgG(2a), IgG(2b), and anti-Smith IgG. Both IRS localized to the kidney after intraperitoneal injection and significantly improved the activity index and chronicity index for lupus nephritis in MRL lpr mice. This was associated with significant reduction of renal glomerular and interstitial macrophage infiltrates and the number of interstitial T cells. Autoimmune lung injury was also attenuated with IRS 661 and IRS 954. These data demonstrate that TLR-7 antagonism, initiated after the onset of autoimmunity, can prevent autoimmune kidney and lung injury in MRL lpr mice. Concomitant blockade of TLR-9 with IRS 954 neutralized the effect of TLR-7 blockade on dsDNA IgG(2a), dsDNA IgG(2b), and Smith antigen autoantibodies but had neither additive nor opposing effects on autoimmune lung and kidney injury. Hence, TLR-7 is proposed as a novel and potential therapeutic target in systemic lupus erythematosus.