| Autor: |
Gordon RA; Department of Immunology and.; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Cosgrove HA; Department of Immunology and.; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Marinov A; Department of Immunology and., Gingras S; Department of Immunology and., Tilstra JS; Department of Immunology and.; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Campbell AM; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA., Bastacky SI; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Kashgarian M; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA., Perl A; Departments of Medicine, Microbiology and Immunology, Biochemistry and Molecular Biology, State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York, USA., Nickerson KM; Department of Immunology and., Shlomchik MJ; Department of Immunology and. |
| Abstrakt: |
Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional KO and chimeric approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr SLE-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated SLE nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Furthermore, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-κB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling. |
