Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients
Deepti Malhotra, … , Peter Barnes, Shyam Biswal
Deepti Malhotra, … , Peter Barnes, Shyam Biswal
Published October 17, 2011
Citation Information: J Clin Invest. 2011;121(11):4289-4302. https://doi.org/10.1172/JCI45144.
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Research Article

Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients

Abstract

Chronic obstructive pulmonary disease (COPD), which is caused primarily by cigarette smoking, is a major health problem worldwide. The progressive decline in lung function that occurs in COPD is a result of persistent inflammation of the airways and destruction of the lung parenchyma. Despite the key role of inflammation in the pathogenesis of COPD, treatment with corticosteroids — normally highly effective antiinflammatory drugs — has little therapeutic benefit. This corticosteroid resistance is largely caused by inactivation of histone deacetylase 2 (HDAC2), which is critical for the transrepressive activity of the glucocorticoid receptor (GR) that mediates the antiinflammatory effect of corticosteroids. Here, we show that in alveolar macrophages from patients with COPD, S-nitrosylation of HDAC2 is increased and that this abolishes its GR-transrepression activity and promotes corticosteroid insensitivity. Cys-262 and Cys-274 of HDAC2 were found to be the targets of S-nitrosylation, and exogenous glutathione treatment of macrophages from individuals with COPD restored HDAC2 activity. Treatment with sulforaphane, a small-molecule activator of the transcription factor nuclear factor erythroid 2–related factor 2 (NRF2), was also able to denitrosylate HDAC2, restoring dexamethasone sensitivity in alveolar macrophages from patients with COPD. These effects of sulforaphane were glutathione dependent. We conclude that NRF2 is a novel drug target for reversing corticosteroid resistance in COPD and other corticosteroid-resistant inflammatory diseases.

Authors

Deepti Malhotra, Rajesh K. Thimmulappa, Nicolas Mercado, Kazuhiro Ito, Ponvijay Kombairaju, Sarvesh Kumar, Jinfang Ma, David Feller-Kopman, Robert Wise, Peter Barnes, Shyam Biswal

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Figure 8

Sulforaphane improves corticosteroid sensitivity by increasing HDAC2 activity in a GSH-dependent manner.

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Sulforaphane improves corticosteroid sensitivity by increasing HDAC2 act...
(A) Total HDAC activity and (B) HDAC2 enzymatic activity in alveolar macrophages treated with or without 5 μM sulforaphane for 16 hours. Enzymatic HDAC2 activity was expressed as “μM of standard.” (C) HDAC2 S-nitrosylation, assessed by biotin-switch assay, in COPD alveolar macrophages after sulforaphane treatment in the presence of 1 mM BSO for 16 hours. (D) ChIP analysis of HDAC2 binding and histone acetylation in the IL-8 promoter of alveolar macrophages after sulforaphane cotreatment with 10 mM TSA in ethanol for 2 hours or with 1 mM BSO for 16 hours in the presence or absence of dexamethasone. (E) Basal and LPS-induced histone acetylation in the promoter of the IL-8 gene in alveolar macrophages after coexposure to sulforaphane and 10 mM TSA in ethanol for 2 hours in the presence or absence of dexamethasone. *P < 0.01 versus vehicle, ANOVA followed by Bonferroni post-test. ‡P < 0.01 as denoted by arrows, Student’s t test. n = 22 patient samples unless otherwise indicated.