4.7 Article

Bim suppresses the development of SLE by limiting myeloid inflammatory responses

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JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 12, 页码 3753-3773

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ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20170479

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资金

  1. American Heart Association [PRE21410010]
  2. National Institutes of Health [K01AR064313, HL108795, AR050250, AR054796, AR064546, AI092490, 1S10OD011996-01]
  3. United States-Israel Binational Science Foundation [2013247]
  4. Rheumatology Research Foundation
  5. Mabel Green Myers Chair of Medicine
  6. National Cancer Institute [P30-CA060553]

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The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. We demonstrate that Bim acts as a molecular rheostat by controlling macrophage function not only in lymphoid organs but also in end organs, thereby preventing the break in tolerance. Mice lacking Bim in myeloid cells (LysM(Cre)Bim(fl/fl)) develop a systemic lupus erythematosus (SLE)-like disease that mirrors aged Bim-/-mice, including loss of marginal zone macrophages, splenomegaly, lymphadenopathy, auto-antibodies (including anti-DNA IgG), and a type I interferon signature. LysM(Cre)Bim(fl/fl) mice exhibit increased mortality attributed to glomerulonephritis (GN). Moreover, the toll-like receptor signaling adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-beta) is essential for GN, but not systemic autoimmunity in LysM(Cre)Bim(fl/fl)mice. Bim-deleted kidney macrophages exhibit a novel transcriptional lupus signature that is conserved within the gene expression profiles from whole kidney biopsies of patients with SLE. Collectively, these data suggest that the Bim may be a novel therapeutic target in the treatment of SLE.

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