The Role of NADPH Oxidase and Neutrophil Extracellular Traps in the Pathogenesis of Systemic Lupus ErythematosusGordon, Rachael (2017) The Role of NADPH Oxidase and Neutrophil Extracellular Traps in the Pathogenesis of Systemic Lupus Erythematosus. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by loss of tolerance to nuclear antigens and tissue destruction. While the sources of autoantigens in SLE are unknown, release of contents from dying cells and/or inadequate clearance of resulting debris are likely possibilities. Prior reports suggest that neutrophil extracellular traps (NETs) and its associated death pathway, NETosis, are sources of autoantigen in SLE. However, we showed that inhibition of NETs by targeting the NADPH oxidase complex, via Cybb-deletion, exacerbated disease in the MRL/lpr model of SLE. To clarify the contribution of NETs in SLE pathogenesis, we employed a genetic approach to delete peptidyl arginine deiminase IV (Padi4) and neutrophil elastase (Elane), two distal mediators of NET formation, in MRL/lpr mice. Both Padi4 and Elane deficiency did alter disease course, directly challenging the concept that NETs promote autoimmunity. Therefore, it remains unknown how NADPH oxidase regulates autoimmunity. NADPH oxidase can constrain inflammation by neutrophil, macrophage, and lymphocyte dependent mechanisms. To identify the cell lineage in which Cybb deficiency drives SLE, we employed bone marrow chimera and conditional knockout approaches to delete Cybb in the myeloid compartment of MRL/lpr mice. Myeloid Cybb deficiency is sufficient to worsen glomerular and interstitial nephritis, suggesting that Cybb is protective in SLE due to a fundamental regulatory activity of Cybb within the myeloid compartment. NADPH oxidase is a critical mediator of LC3-associated phagocytosis (LAP), which is important for the clearance of dead cells by macrophages. As Cybb modulates SLE pathogenesis by its function in myeloid cells, we assessed LAP in lupus. To test the hypothesis that exacerbated SLE in Cybb-deficient mice is due to defective LAP, we genetically deleted another critical LAP mediator, Rubicon, in Cybb-sufficient and Cybb-deficient SLE prone mice. Unexpectedly, Rubicon deficiency increased the lifespan and ameliorated renal disease in Cybb-deficient MRL/lpr mice. Strikingly, Rubicon deficiency reduced the autoantibody responses to RNA associated autoantigens. These data suggest that a defect in LAP is not a major driver of SLE and highlights RUBICON as a novel mediator of lupus pathogenesis. The mechanism by which myeloid Cybb regulates SLE remains enigmatic and requires further investigation. Share
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