Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation and development of autoantibodies against nucleic acids (NAs). SLE pathogenesis is not fully understood but genomic studies support an interplay between innate and adaptive immunity. Pathogenic loops involving immune complex(IC)-containing NAs that activate innate immune cells such as dendritic cells (DCs), platelets and neutrophils through the endosomal TLR pathway result in plasmacytoid DC (pDC) activation and release of type I IFN. Excessive production and/or sensing of NAs is emerging as a fundamental and upstream event in SLE, and over-expression of IFN-inducible transcriptional signatures is a universal finding, especially in early onset SLE. We and others recently reported that neutrophils release DNA-protein complexes that activate pDCs, thus acting as Danger-Associated Molecular Patterns (DAMPs). DAMPS are extruded upon neutrophil activation with SLE immune complexes (ICs) and directly activate pDCs in an FcR-independent and TLR9-dependent manner. Our preliminary data now show that these DAMPs are composed of damaged (oxidized) mitochondrial DNA-protein complexes (mtDAMPs) released upon type I IFN and anti-Sm/RNP mediated endosomal TLR7 activation of neutrophils. This combination of stimuli impairs the detoxification of oxidized mtDNA through lysosomal degradation, which is a fundamental step leading to the extrusion of interferogenic mtDAMPs. Here, we propose 1) to characterize the basic mechanisms that lead to neutrophil mitochondrial damage and release of mtDAMPs in SLE, 2) to identify the interferogenic components of mtDAMPs and the mechanisms responsible for their internalization in pDCs, and 3) to characterize the effects of SLE mtDAMPs on non-hemopoietic cells that become the target of inflammation in SLE, especially endothelial cells. Overall, these studies will provide a better understanding of how breakdown of tolerance to NAs and dysregulation of the IFN pathway are interconnected and amplify each other. These studies will bring novel insight into SLE autoantibody pathogenic roles and perpetuation of IFN-amplification loops

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Our work supports a previously unsuspected role for neutrophils as a link between lupus-specific nucleic acid-recognizing antibodies and amplification loops for type I IFN production and eventually B cell help. Completion of the project goals will lead to better understanding of these pathways and to the identification of novel therapeutic targets.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
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Baylor Research Institute
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