Superoxide Production by NADPH Oxidase Intensifies Macrophage Antiviral Responses during Diabetogenic Coxsackievirus Infection

• Published in: The Journal of immunology (1950) 2018-01, Vol.200 (1), p.61-70
• Main Authors: Burg, Ashley R, Das, Shaonli, Padgett, Lindsey E, Koenig, Zachary E, Tse, Hubert M
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autoimmune diseases; Bone marrow; Cells, Cultured; Chemokines; Chemokines - metabolism; Coxsackievirus; Coxsackievirus Infections - complications; Coxsackievirus Infections - immunology; Coxsackieviruses; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - immunology; Disease Models, Animal; Double-stranded RNA; Enterovirus - immunology; Humans; Infections; Inflammation; Inflammation Mediators - metabolism; Insulin-Secreting Cells - immunology; Macrophages; Macrophages - immunology; Macrophages - virology; Mice; Mice, Inbred NOD; NAD(P)H oxidase; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Oxidation; Oxidative Stress; Pancreas; RNA, Viral - immunology; Rodents; Signal Transduction; STAT1 Transcription Factor - metabolism; Superoxide; Superoxides - metabolism; Transcription; Viruses
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700478

Coxsackievirus B infections are suspected environmental triggers of type 1 diabetes (T1D) and macrophage antiviral responses may provide a link to virus-induced T1D. We previously demonstrated an important role for NADPH oxidase (NOX)-derived superoxide production during T1D pathogenesis, as NOX-deficient NOD mice (NOD. ) were protected against T1D due, in part, to impaired proinflammatory TLR signaling in NOD. macrophages. Therefore, we hypothesized that loss of NOX-derived superoxide would dampen diabetogenic antiviral macrophage responses and protect from virus-induced diabetes. Upon infection with a suspected diabetogenic virus, Coxsackievirus B3 (CB3), NOD. mice remained resistant to virus-induced autoimmune diabetes. A concomitant decrease in circulating inflammatory chemokines, blunted antiviral gene signature within the pancreas, and reduced proinflammatory M1 macrophage responses were observed. Importantly, exogenous superoxide addition to CB3-infected NOD. bone marrow-derived macrophages rescued the inflammatory antiviral M1 macrophage response, revealing reduction-oxidation-dependent mechanisms of signal transducer and activator of transcription 1 signaling and dsRNA viral sensors in macrophages. We report that superoxide production following CB3 infection may exacerbate pancreatic β cell destruction in T1D by influencing proinflammatory M1 macrophage responses, and mechanistically linking oxidative stress, inflammation, and diabetogenic virus infections.