Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice.
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 microg 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-alpha (IFNalpha), interleukin-12 (IL-12), IL-6, and IFNgamma, 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.


CONCLUSIONS
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.
Sadanaga
Atsushi
A
Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakashima
Hitoshi
H
Akahoshi
Mitsuteru
M
Masutani
Kohsuke
K
Miyake
Katsuhisa
K
Igawa
Takashi
T
Sugiyama
Naonobu
N
Niiro
Hiroaki
H
Harada
Mine
M
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007369:Interferon Inducers / Q000009:adverse effects; D016898:Interferon-alpha / Q000097:blood; D007668:Kidney / Q000473:pathology; D008024:Ligands; D008168:Lung / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics* / Q000502:physiology*; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D011070:Poly I-C / Q000009:adverse effects; D012469:Salivary Glands / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000502:physiology
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007369:Interferon Inducers; D016898:Interferon-alpha; D008024:Ligands; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C