Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice
Atsushi Sadanaga
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Hitoshi Nakashima
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JapanSearch for more papers by this authorMitsuteru Akahoshi
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKohsuke Masutani
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKatsuhisa Miyake
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorTakashi Igawa
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorNaonobu Sugiyama
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorHiroaki Niiro
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
Search for more papers by this authorMine Harada
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorAtsushi Sadanaga
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Hitoshi Nakashima
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, JapanSearch for more papers by this authorMitsuteru Akahoshi
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKohsuke Masutani
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKatsuhisa Miyake
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorTakashi Igawa
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorNaonobu Sugiyama
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorHiroaki Niiro
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
Search for more papers by this authorMine Harada
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorAbstract
Objective
To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis.
Methods
MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll-like receptors (TLRs) except TLR-3. We therefore generated MyD88-knockout (MyD88-KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88-independent pathway in autoimmune nephritis, we injected MyD88-KO MRL/lpr mice intraperitoneally with either poly(I-C) (50 or 100 μg per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters.
Results
In comparison with wild-type mice, MyD88-KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti–double-stranded DNA (anti-dsDNA) and production of cytokines, including interferon-α (IFNα), interleukin-12 (IL-12), IL-6, and IFNγ, in splenocytes were significantly reduced in MyD88-KO MRL/lpr mice. Interestingly, MyD88-KO MRL/lpr mice that had been treated with the MyD88-independent TLR-3 ligand poly(I-C) showed an almost complete reversion to the features of wild-type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti-dsDNA titers and increased cytokine production in splenocytes.
Conclusion
The findings indicate that both MyD88-dependent and MyD88-independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/lpr mice.
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