TET1 Protects the Lungs from Diesel Exhaust Particle-Induced Inflammation and Abnormal Function.

Rationale: Diesel exhaust particles (DEP) are a major contributor to air pollution-associated asthma exacerbations, promoting oxidative stress, airway inflammation, and Th17-skewed immune responses. Although epigenetic mechanisms are increasingly recognized as key modulators of environmental lung disease, the role of the DNA demethylation enzyme TET1 in DEP-induced airway dysfunction remains poorly defined. We investigated the contribution of TET1 to epithelial and airway responses to DEP using complementary human and murine models. Methods: TET1 was silenced in human bronchial epithelial cells (HBECs) followed by DEP exposure, and transcriptomic alterations and cytokine production were assessed. In parallel, Tet1 heterozygous (Tet1 Results: Loss of TET1 markedly amplified DEP-induced transcriptional responses in HBECs, characterized by enhanced pro-inflammatory signaling and suppression of AhR-dependent xenobiotic detoxification genes. Conclusions: These findings suggest that epigenetic modulation of TET1-dependent pathways may represent a novel strategy to reduce susceptibility to pollution-induced airway disease. Collectively, our data identify TET1 as a central epigenetic regulator integrating detoxification and inflammatory programs in the airway epithelium during environmental exposure.