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 ^+/- ) and wild‑type littermates were subjected to repeated intratracheal DEP exposure to evaluate airway hyperresponsiveness, lung inflammation, immune cell recruitment, and cytokine expression. Mechanistically targeted interventions supporting TET activity, inhibiting Aryl Hydrocarbon Receptor (AhR) signaling, or limiting mitochondrial oxidative stress were evaluated in vitro and in vivo . 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. In vivo , TET1 ^+/- mice exhibited increased airway hyperresponsiveness, neutrophilic inflammation, and elevated expression of neutrophil chemokine and Th17‑associated cytokines following DEP exposure. Notably, pharmacologic AhR inhibition and reduction of oxidative stress attenuated inflammatory cytokine expression in vitro and partially mitigated DEP-induced airway inflammation and hyperresponsiveness in vivo . 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. Total Word Count: 6,314.