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@PHDTHESIS{Offermann:258582,
      author       = {Offermann, Nina},
      title        = {{R}ole of the proton channel {HVCN}1 in the regulation of
                      neutrophil activation},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2023-00611},
      pages        = {126},
      year         = {2023},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2023},
      abstract     = {Excessive neutrophil activation is a feature of many
                      inflammatory diseases. Neutrophils from affected patients
                      are prone to release reactive oxygen species (ROS) and toxic
                      granule proteins or to undergo NETosis, a special form of
                      cell death characterized by the release of extracellular DNA
                      traps (NETs). Indeed, neutrophils have been shown to play a
                      critical role in the development of autoimmune diseases, as
                      NETs provide autoantigens, such as double-stranded DNA in
                      systemic lupus erythematosus (SLE) or myeloperoxidase (MPO)
                      in ANCA-associated vasculitis. Nonetheless, the molecular
                      switches regulating neutrophil effector functions remain to
                      be further characterized.HVCN1 is the only voltage-gated
                      proton channel in mammals that regulates pH and membrane
                      potential during neutrophil activation. Its function
                      supports the electrogenic activity of the ROS-generating
                      enzyme NADPH oxidase. Therefore, NADPH oxidase-dependent ROS
                      production is significantly impaired in the absence of
                      HVCN1. However, not much is known about how HVCN1 regulates
                      neutrophil downstream functions.Therefore, in the first part
                      of my thesis, I further investigated the role of HVCN1 in
                      neutrophils. I demonstrated that PMA-stimulated NETosis and
                      MPO release were significantly increased in HVCN1−/−
                      neutrophils. Fittingly, HVCN1−/− neutrophils showed
                      atypical mobilization of calcium, increased histone
                      citrullination, and high mitochondrial ROS caused by
                      calcium-dependent mitochondrial depolarization. Increased
                      NETosis, MPO release, and mitochondria ROS could be rescued
                      by intracellular calcium chelation but not by antioxidants,
                      suggesting that calcium is the primary determinant of
                      increased NETosis susceptibility in HVCN1−/−
                      neutrophils.I further examined the consequences of HVCN1
                      deficiency in vivo. In agreement with previous reports,
                      young HVCN1−/− mice did not exhibit a pathogenic
                      phenotype, however we detected a mild (auto-) inflammatory
                      phenotype in aged, female HVCN1−/− mice. Likewise,
                      HVCN1−/− mice showed more severe pathology in two models
                      of inflammation. Correspondingly, we found HVCN1 to be
                      downregulated in neutrophils from SLE patients in two
                      separate datasets. This is the first study to show that
                      HVCN1 deficiency increases the inflammatory capacity of
                      murine neutrophils in vitro and in vivo, suggesting that
                      downregulation of HVCN1 may have implications for human
                      disease.},
      cin          = {AG Capasso / Library and Information Services},
      cid          = {I:(DE-2719)1013033 / I:(DE-2719)1040260},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5-71080},
      url          = {https://pub.dzne.de/record/258582},
}