Glutaredoxin 2 Reduces Asthma-Like Acute Airway Inflammation in Mice

Frontiers in Immunology

Holger Garn¹  Eva-Maria Hanschmann³  Christina Hecker³  Carsten Berndt³  W. Bertrams⁴  Christopher H. Lillig⁵  Christoph Hudemann⁶ 

[1] Biochemical Pharmacological Center (BPC)–Translational Inflammation Research Division, Philips Universität Marburg, Member of the German Center for Lung Research (DZL) and the Universities of Giessen and Marburg Lung Center (UGMLC), Marburg, Germany;Department of Dermatology and Allergology, Philipps Universität Marburg, Marburg, Germany;Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany;Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany;Institute for Medical Biochemistry and Molecular Biology, University of Greifswald, Greifswald, Germany;Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg, Germany;

关键词: airway inflammation;    asthma;    redox;    oxidative dysbalance;    reactive oxygen species;   

DOI  :  10.3389/fimmu.2020.561724

来源: DOAJ

【 摘 要 】

Endogenous redox systems not only counteract oxidative damage induced by high levels of hydroxyl radicals (OH·) under pathological conditions, but also shape redox signaling as a key player in the regulation of physiological processes. Second messengers like hydrogen peroxide and nitric oxide, as well as redox enzymes of the Thioredoxin (Trx) family, including Trxs, glutaredoxins (Grxs), and peroxiredoxins (Prxs) modulate reversible, oxidative modifications of proteins. Thereby redox regulation is part of various cellular processes such as the immune response and Trx proteins have been linked in different disorders including inflammatory diseases. Here, we have analyzed the protein distribution of representative oxidoreductases of the Trx fold protein family—Trx1, Grx1, Grx2, and Prx2—in a murine model of allergic asthma bronchiale, as well as their potential therapeutic impact on type-2 driven airway inflammation. Ovalbumin (OVA) sensitization and challenge using the type-2 prone Balb/c mouse strain resulted in increased levels of all investigated proteins in distinct cellular patterns. While concomitant treatment with Grx1 and Prx2 did not show any therapeutic impact on the outcome of the disease, Grx2 or Trx1 treatment before and during the OVA challenge phase displayed pronounced protective effects on the manifestation of allergic airway inflammation. Eosinophil numbers and the type-2 cytokine IL-5 were significantly reduced while lung function parameters profoundly improved. The number of macrophages in the bronchoalveolar lavage (BAL) did not change significantly, however, the release of nitric oxide that was linked to airway inflammation was successfully prevented by enzymatically active Grx2 ex vivo. The Grx2 Cys-X-X-Ser mutant that facilitates de-/glutathionylation, but does not catalyze dithiol/disulfide exchange lost the ability to protect from airway hyper reactivity and to decrease NO release by macrophages, however, it reduced the number of infiltrating immune cells and IL-5 release. Altogether, this study demonstrates that specific redox proteins and particular enzyme activities protect against inflammatory damage. During OVA-induced allergic airway inflammation, administration of Grx2 exerts beneficial and thus potentially therapeutic effects.

【 授权许可】

Unknown