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Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus.
Leibler, Claire; John, Shinu; Elsner, Rebecca A; Thomas, Kayla B; Smita, Shuchi; Joachim, Stephen; Levack, Russell C; Callahan, Derrick J; Gordon, Rachael A; Bastacky, Sheldon; Fukui, Ryutaro; Miyake, Kensuke; Gingras, Sebastien; Nickerson, Kevin M; Shlomchik, Mark J.
Affiliation
  • Leibler C; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • John S; Department of Nephrology, Henri Mondor Hospital, Assistance-Publique-Hopitaux de Paris, Paris Est Creteil University, INSERM, IMRB, Creteil, France.
  • Elsner RA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA.
  • Thomas KB; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Smita S; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Joachim S; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Levack RC; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Callahan DJ; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Gordon RA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Bastacky S; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Fukui R; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Miyake K; Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Tokyo, Japan.
  • Gingras S; Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Shirokanedai, Tokyo, Japan.
  • Nickerson KM; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • Shlomchik MJ; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Nat Immunol ; 23(10): 1457-1469, 2022 10.
Article in En | MEDLINE | ID: mdl-36151396
ABSTRACT
In lupus, Toll-like receptor 7 (TLR7) and TLR9 mediate loss of tolerance to RNA and DNA, respectively. Yet, TLR7 promotes disease, while TLR9 protects from disease, implying differences in signaling. To dissect this 'TLR paradox', we generated two TLR9 point mutants (lacking either ligand (TLR9K51E) or MyD88 (TLR9P915H) binding) in lupus-prone MRL/lpr mice. Ameliorated disease of Tlr9K51E mice compared to Tlr9-/- controls revealed a TLR9 'scaffold' protective function that is ligand and MyD88 independent. Unexpectedly, Tlr9P915H mice were more protected than both Tlr9K51E and Tlr9WT mice, suggesting that TLR9 also possesses ligand-dependent, but MyD88-independent, regulatory signaling and MyD88-mediated proinflammatory signaling. Triple-mixed bone marrow chimeras showed that TLR9-MyD88-independent regulatory roles were B cell intrinsic and restrained differentiation into pathogenic age-associated B cells and plasmablasts. These studies reveal MyD88-independent regulatory roles of TLR9, shedding light on the biology of endosomal TLRs.
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Full text: 1 Database: MEDLINE Main subject: Toll-Like Receptor 9 / Toll-Like Receptor 7 Limits: Animals Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2022 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Toll-Like Receptor 9 / Toll-Like Receptor 7 Limits: Animals Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2022 Type: Article Affiliation country: United States