title: Proteinase-activated receptor-2 agonist activates anti-influenza mechanisms and modulates IFNγ-induced antiviral pathways in human neutrophils.
abstract: Proteinase-activated receptor-2 (PAR2) is expressed by human leukocytes and participates in the development of inflammatory diseases. Recent studies demonstrated an ability of PAR2 agonist to enhance IFNγ-induced antiviral responses of human leukocytes. However, the precise cellular antiviral defense mechanisms triggered in leukocytes after stimulation with IFNγ and/or PAR2 agonist remain elusive. Therefore, we aimed to identify neutrophil defense mechanisms involved in antiviral resistance. Here we demonstrated that PAR2 agonist enhanced IFNγ-related reduction of influenza A virus (IAV) replication in human neutrophils. PAR2-mediated decrease in IAV replication was associated with reduced NS-1 transcription. Moreover, PAR2-dependent neutrophil activation resulted in enhanced myeloperoxidase degranulation and extracellular myeloperoxidase disrupted IAV. The production of ROS was elevated in response to PAR2 activation. Interestingly, IFNγ did not influence both effects: PAR2 agonist-triggered myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which are known to limit IAV infections. In contrast, orthomyxovirus resistance gene A (MxA) protein expression was synergistically elevated through PAR2 agonist and IFNγ in neutrophils. Altogether, these findings emphasize two PAR2-controlled antiviral mechanisms that are independent of or modulated by IFNγ.
authors.affiliation: Department of Dermatology, Heinrich-Heine University, 40225 Düsseldorf, Germany.
authors.forename: Micha
authors.initials: M
authors.lastname: Feld
authors.forename: Victoria
authors.initials: V
authors.lastname: Shpacovitch
authors.forename: Christina
authors.initials: C
authors.lastname: Ehrhardt
authors.forename: Michaela
authors.initials: M
authors.lastname: Fastrich
authors.forename: Tobias
authors.initials: T
authors.lastname: Goerge
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D015550:Cell Degranulation; D006801:Humans; D007111:Immunity, Cellular; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D007371:Interferon-gamma / Q000276:immunology*; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists*; D017361:Viral Nonstructural Proteins / Q000235:genetics; D014779:Virus Replication
chemical_list: C085820:INS1 protein, influenza virus; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044464:Receptor, PAR-2; D017361:Viral Nonstructural Proteins; C113425:cinnamoyl-LIGRLO-amide; D007371:Interferon-gamma; D009195:Peroxidase; D015088:2',5'-Oligoadenylate Synthetase