IFN regulatory factor 5 is required for disease development in the FcgammaRIIB-/-Yaa and FcgammaRIIB-/- mouse models of systemic lupus erythematosus.
Polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus. However, the biological role of IRF5 in lupus pathogenesis has not previously been tested in an animal model. In this study, we show that IRF5 is absolutely required for disease development in the FcgammaRIIB(-/-)Yaa and FcgammaRIIB(-/-) lupus models. In contrast to IRF5-sufficient FcgammaRIIB(-/-)Yaa mice, IRF5-deficient FcgammaRIIB(-/-)Yaa mice do not develop lupus manifestations and have a phenotype comparable to wild-type mice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5 heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I IFN, IFN-alpha, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgammaRIIB(-/-)Yaa mice lacking the type I IFN receptor subunit 1. Unlike the IRF5-deficient and IRF5-heterozygous FcgammaRIIB(-/-)Yaa mice, type I IFN receptor subunit 1-deficient FcgammaRIIB(-/-)Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgammaRIIB(-/-) mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgammaRIIB(-/-)Yaa mice are not due only to inhibition of the enhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I IFN production.
Richez
Christophe
C
Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Yasuda
Kei
K
Bonegio
Ramon G
RG
Watkins
Amanda A
AA
Aprahamian
Tamar
T
Busto
Patricia
P
Richards
Rocco J
RJ
Liu
Chih Long
CL
Cheung
Regina
R
Utz
Paul J
PJ
Marshak-Rothstein
Ann
A
Rifkin
Ian R
IR
D000818:Animals; D015551:Autoimmunity; D004195:Disease Models, Animal; D005838:Genotype; D050835:Interferon Regulatory Factors / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017452:Receptors, IgG / Q000172:deficiency*
C499172:Fcgr2b protein, mouse; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; C498178:Irf5 protein, mouse; D017452:Receptors, IgG