Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis.
Multiple genetic factors contribute to the clinical variability of spontaneous systemic lupus erythematosus (SLE) but their role in drug-induced SLE remain largely unknown. Hydrocarbon oil-induced SLE depends on mesothelial cell apoptosis and Toll-like receptor (TLR)-7-mediated induction of type I interferons. Hence, we hypothesized that TIR8/SIGIRR, an endogenous TLR inhibitor, prevents oil-induced SLE. Sigirr-deficient dendritic cells expressed higher TLR7 mRNA levels and TLR7 activation resulted in increased IL-12 production in vitro. In vivo, lack of SIGIRR increased surface CD40 expression on spleen CD11c(+) dendritic cells and MX-1, TNF, IL-12, BAFF and BCL-2 mRNA expression 6 months after pristane injection. Spleen cell counts of CD4(-)/CD8(-) 'autoreactive' T cells and B220(+) B cells were also increased in Sigirr(-/-) mice. Serum autoantibody analysis revealed that Sigirr deficiency specifically enhanced the production of rheumatoid factor (from 4 months of age) and anti-snRNP IgG (from 5 months of age), while anti-Smith IgG or anti-dsDNA IgG were independent of the Sigirr genotype. This effect was sufficient to significantly aggravate lupus nephritis in Sigirr-deficient mice. Structure model prediction identified the BB loop of SIGIRR's intracellular TIR domain to interact with TLR7 and MyD88. BB loop deletion was sufficient to completely abrogate SIGIRR's inhibitory effect on TLR7 signalling. Thus, TIR8/SIGIRR protects from hydrocarbon oil-induced lupus by suppressing the TLR7-mediated activation of dendritic cells, via its intracellular BB loop.
Lech
Maciej
M
Medizinische Poliklinik, University of Munich, Germany.
Skuginna
Veronika
V
Kulkarni
Onkar P
OP
Gong
Jing
J
Wei
Tiandi
T
Stark
Robert W
RW
Garlanda
Cecilia
C
Mantovani
Alberto
A
Anders
Hans-Joachim
HJ
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001202:Ascitic Fluid / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D008181:Lupus Nephritis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D010641:Phenotype; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D017385:Sequence Homology; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013729:Terpenes; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D016207:Cytokines; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D013729:Terpenes; D051199:Toll-Like Receptor 7; C507780:Myd88 protein, mouse; C546891:SIGIRR protein, human; C434984:TIRAP protein, human; C495348:TLR7 protein, human; C484529:SIGIRR protein, mouse; C477038:Tlr7 protein, mouse; C009042:pristane