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The transcriptional repressor Gfi1 prevents lupus autoimmunity by restraining TLR7 signaling

Abstract : 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.
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https://hal-amu.archives-ouvertes.fr/hal-02008644
Contributor : Benoit Desnues <>
Submitted on : Tuesday, February 5, 2019 - 6:02:57 PM
Last modification on : Thursday, March 12, 2020 - 2:54:10 PM

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Benoit Desnues, Amanda Macedo, Diana Ordoñez-Rueda, Annie Roussel-Queval, Bernard Malissen, et al.. The transcriptional repressor Gfi1 prevents lupus autoimmunity by restraining TLR7 signaling. European Journal of Immunology, Wiley-VCH Verlag, 2016, 46 (12), pp.2801-2811. ⟨10.1002/eji.201646573⟩. ⟨hal-02008644⟩

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