Aldehyde dehydrogenase 2 deficiency reinforces formaldehyde-potentiated pro-inflammatory responses and glycolysis in macrophages

Aldehyde dehydrogenase 2 (ALDH2) deficiency caused by genetic variant is present in more than 560 million people of East Asian descent, which can be identified by apparent facial flushing from acetaldehyde accumulation after consuming alcohol. Recent findings indicated that ALDH2 also played a critical role in detoxification of formaldehyde (FA). Our previous studies showed that FA could enhance macrophagic inflammatory responses through the induction of HIF-1 alpha-dependent glycolysis. In the present study, pro-inflammatory responses and glycolysis promoted by 0.5 mg/m(3) FA were found in mice with Aldh2 gene knockout, which was confirmed in the primary macrophages isolated from Aldh2 gene knockout mice treated with 50 mu M FA. FA at 50 and 100 mu M also induced stronger dose-dependent increases of pro-inflammatory responses and glycolysis in RAW264.7 murine macrophages with knock-down of ALDH2, and the enhanced effects induced by 50 mu M FA was alleviated by inhibition of HIF-1 alpha in RAW264.7 macrophages with ALDH2 knock-down. Collectively, these results clearly demonstrated that ALDH2 deficiency reinforced pro-inflammatory responses and glycolysis in macrophages potentiated by environmentally relevant concentration of FA, which may increase the susceptibility to inflammation and immunotoxicity induced by environmental FA exposure.