Toll-like receptor-7 modulates immune complex glomerulonephritis.
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 MRLlpr/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 MRLlpr/lpr mice. TLR7 ligation activated monocytes and dendritic cells, both isolated from MRLlpr/lpr mice, to secrete IFN-alpha, IL-12p70, IL-6, and CCL2. In vivo, a single injection of the TLR7 ligand imiquimod increased serum levels of IL-12p70, IFN-alpha, and IL-6. A course of 25 microg of imiquimod given every other day from week 16 to 18 of age aggravated lupus nephritis in MRLlpr/lpr mice. This was associated with increased glomerular immune complex deposits as well as interstitial expression of CCL2 in imiquimod-treated MRLlpr/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.
Pawar
Rahul D
RD
Nephrological Center, Medical Policlinic, University of Munich, Munich, Germany.
Patole
Prashant S
PS
Zecher
Daniel
D
Segerer
Stephan
S
Kretzler
Matthias
M
Schlöndorff
Detlef
D
Anders
Hans-Joachim
HJ
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation; D000936:Antigen-Antibody Complex / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology*; D000077271:Imiquimod; D007105:Immune Complex Diseases / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008181:Lupus Nephritis / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D012333:RNA, Messenger / Q000032:analysis; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000502:physiology*
D000634:Aminoquinolines; D000936:Antigen-Antibody Complex; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D018664:Interleukin-12; D000077271:Imiquimod