Protein S-glutathionylation (PSSG), a reversible posttranslational modification of reactive cysteines, recently emerged as a regulatory mechanism that affects diverse cell-signaling cascades. The extent of cellular PSSG is controlled by the oxidoreductase glutaredoxin-1 (Grx1), a cytosolic enzyme that specifically de-glutathionylates proteins. Here, we sought to evaluate the impact of the genetic ablation of Grx1 on PSSG and on LPS-induced lung inflammation. In response to LPS, Grx1 activity increased in lung tissue and bronchoalveolar lavage (BAL) fluid in WT(WT) mice compared with PBS control mice. Glrx1(-/-) mice consistently showed slight but statistically insignificant decreases in total numbers of inflammatory cells recovered by BAL. However, LPS-induced concentrations of IL-1 beta, TNF-alpha, IL-6, and Granulocyte/Monocyte Colony-Stimulating Factor (GM-CSF) in BAL were significantly decreased in Glrx1(-/-) mice compared with WT mice. An in situ assessment of PSSG reactivity and a biochemical evaluation of PSSG content demonstrated increases in the lung tissue of Glrx1(-/-) animals inresponse to LPS, compared with WT mice or PBS control mice. We also demonstrated that PSSG reactivity was prominent in alveolar macrophages (AMs). Comparative BAL analyses from WT and Glrx12/2 mice revealed fewer and smaller AMs in Glrx12/2 mice, which showed a significantly decreased expression of NF-kappa B family members, impaired nuclear translocation of RelA, and lower levels of NF-kappa B-dependent cytokines after exposure toLPS, compared with WT cells. Taken together, these results indicate that Grx1 regulates the production of inflammatory mediators through control of S-glutathionylation-sensitive signaling pathways such as NF-kappa B, and that Grx1 expression is critical to the activation of AMs.
|Journal||American Journal of Respiratory Cell and Molecular Biology|
|Publication status||Published - 1 Jan 2011|
Aesif, S. W., Anathy, V., Kuipers, I., Guala, A. S., Reiss, J. N., Ho, Y. S., & Janssen-Heininger, Y. M. W. (2011). Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced lung inflammation and alveolar macrophage activation. American Journal of Respiratory Cell and Molecular Biology, 44(4), 491-499. https://doi.org/10.1165/rcmb.2009-0136OC