The transcriptional repressor Gfi1 prevents lupus autoimmunity by restraining TLR7 signaling.
The transcriptional repressor growth factor independence 1 (Gfi1) is important in myeloid and lymphoid differentiation. In the current study we evaluated the involvement of Gfi1 in systemic lupus erythematosus (SLE). We found that Genista mice, which carry a hypomorphic mutation in the gfi1 gene or Gfi1-deficient (Gfi1-/-) mice develop signs of spontaneous lupus autoimmunity, including increased serum levels of IgM and IgG2a, autoantibodies against RNA and DNA, glomerular immunodeposits and increased frequencies of plasmablasts, germinal center (GC) B cells and age-associated B cells (ABCs). On the contrary, Genista mice deprived of TLR7 did not show any of these phenotypes, suggesting that the observed lupus autoimmunity in Genista mice is TLR7-dependent. Moreover, Genista mice showed an increased activation of dendritic cells (DCs), B and T cells that was dependent on TLR7 for DCs and B cells, but not for T cells. Upon TLR7 or TLR4 stimulation Genista DCs produced increased amounts of TNF, IL-6 and IFN-β and showed increased NF-κB phosphorylation and IRF7 nuclear translocation, suggesting that Gfi1 controls the NF-κB and type I IFN signaling pathway downstream of TLRs. Our data reveal that Gfi1 plays a critical role in the prevention of spontaneous lupus autoimmunity by negatively regulating TLR7 signaling.
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Benoit
B
Desnues
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Amanda B
AB
Macedo
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Diana
D
Ordoñez-Rueda
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Annie
A
Roussel-Queval
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Bernard
B
Malissen
Unité des Anticorps en Thérapie et Pathologie, Département d'Immunologie, Institut Pasteur, Paris, France.|INSERM, U1222, Paris, France.
Pierre
P
Bruhns
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Marie
M
Malissen
Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France.
Lena
L
Alexopoulou
D000818:Animals; D015551:Autoimmunity; D001854:Bone Marrow Cells / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000235:genetics; D051200:Toll-Like Receptor 8 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; D008562:Membrane Glycoproteins; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014157:Transcription Factors
Animal model; Dendritic cells; Growth factor independence 1 (Gfi1); Innate immunity; Systemic lupus erythematosus (SLE); Toll-like receptor 7 (TLR7)