4-OI improves mitochondria-associated endoplasmic reticulum membrane dysfunction by regulating MFN2 through Nrf2 transcription and alleviates airway inflammation in asthma exposed to PM2.5 early in life.

Abstract

BACKGROUND: Asthma is a disease that still lacks effective preventive measures with distinctive pathologicfeatures, particularly inflammation, oxidative stress, apoptosis and endoplasmic reticulum (ER) stress. 4-Octyl itaconate (4-OI) has been reported to possess immunomodulatory, anti-inflammatory and antioxidant properties. METHODS: In this study, we evaluated the efficacy of 4-OI in airway inflammation and oxidative lung injury in asthmatic mice exposed to PM2.5 using the ovalbumin (OVA)+ PM2.5-induced asthma model in BALB/c mice. In addition, we further evaluated the role of 4-OI in protecting BEAS-2B cells from PM2.5 induction using an in vitro model of asthma. RESULTS: The results showed that 4-OI attenuated airway inflammatory cell infiltration and the levels of mouse whole lung lavage fluid inflammatory factors, and decreased the levels of MDA and ROS, while increasing the activity of SOD. Meanwhile, in in vitro experiments, it was further demonstrated that 4-OI transcriptionally regulated MFN2 via Nrf2, which reduced the intracellular and mitochondrial ROS content, and the fluorescence intensities of Mito Tracker Red+ calnexin+ and MFN2+PERK+ were also significantly reduced. Fluo-3 AM experiment showed that 4-OI reduced Ca2+ concentration by regulating MFN2 through Nrf2 transcription. In addition, the protein expression of MFN1, MFN2, Bcl-2, and pro-Caspase3 was significantly elevated and that of PERK, GRP78, CHOP, Caspase12, Bax, and cleaved-Caspase3 was significantly decreased by Western Blot. CONCLUSIONS: In summary, our research demonstrated found that 4-OI improved the dysfunction of mitochondria-associated endoplasmic reticulum membranes by modulating MFN2 via Nrf2 transcription, thereby reducing the inflammatory response in asthmatic airways during early exposure to PM2.5.

Key Findings

• 4-OI attenuated airway inflammatory cell infiltration and decreased inflammatory factors in lung lavage fluid.
• 4-OI reduced levels of MDA and ROS while increasing SOD activity in asthmatic mice exposed to PM2.5.
• 4-OI transcriptionally regulated MFN2 via Nrf2, reducing intracellular and mitochondrial ROS and improving mitochondria-associated ER membrane function.
• 4-OI decreased ER stress markers (PERK, GRP78, CHOP, Caspase12) and pro-apoptotic proteins (Bax, cleaved-Caspase3) while increasing anti-apoptotic proteins (Bcl-2, pro-Caspase3).
• 4-OI reduced intracellular Ca2+ concentration by regulating MFN2 through Nrf2 transcription.

Clinical Significance

Citation

Xu Jiaxin, Wang Lei, Zhou Ruiet al.. 4-OI improves mitochondria-associated endoplasmic reticulum membrane dysfunction by regulating MFN2 through Nrf2 transcription and alleviates airway inflammation in asthma exposed to PM2.5 early in life. Inhalation toxicology. 2026-Mar-28.