Premium
Activation of toll‐like receptor‐9 induces progression of renal disease in MRL‐Fas(lpr) mice
Author(s) -
Anders HansJoachim,
Vielhauer Volker,
Eis Vaclav,
Linde Yvonne,
Kretzler Matthias,
Perez de Lema Guillermo,
Strutz Frank,
Bauer Stefan,
Rutz Mark,
Wagner Hermann,
Gröne HermannJosef,
Schlöndorff Detlef
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0646fje
Subject(s) - tlr9 , lupus nephritis , immunology , nephritis , autoimmunity , glomerulonephritis , medicine , nephropathy , chemokine , systemic lupus erythematosus , toll like receptor 9 , immune system , kidney , biology , endocrinology , dna methylation , disease , biochemistry , gene expression , diabetes mellitus , gene
How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll‐like receptor (TLR)‐9 activation by exogenous or endogenous CpG‐DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG‐ oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli ( E. coli ) on the course of nephritis in MRL lpr/lpr mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG‐ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL lpr/lpr mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL lpr/lpr mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up‐regulated CCL5/RANTES mRNA upon stimulation with CpG‐ ODN in vitro. In vivo both E. coli DNA and CpG‐ODN increased serum DNA autoantibodies of the IgG 2a isotype in MRL lpr/lpr mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG‐ODN increased renal CCL2/MCP‐1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC‐ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG‐DNA‐induced progression of lupus nephritis.