Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction

Abnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 level in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease.

Research highlights
► HDAC2 is a critical factor in inhaled toxicant-mediated lung inflammation especially in regulating the anti-inflammatory effects of glucocorticoids.
► Loss of Nrf2 resulted in decreased HDAC2 in lung, and increased inflammatory lung response which was not reversed by steroid.
► Steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis.
► Steroid resistance via Nrf2-HDAC2 axis leads to abnormal inflammatory response which is seen in patients with chronic inflammatory diseases.
► Understanding the redox regulation of Nrf2-HDAC2 may lead to better therapies for patients who are refractory/insensitive to steroid treatments.