C70-32 Inhibition Of Histone H3 Sumoylation Alleviates Airway Epithelial Barrier Dysfunction In Asthma

Rationale

Epigenetic modifications, including histone acetylation and DNA methylation, have been well documented to regulate airway epithelial barrier function in asthma. However, whether histone SUMOylation is involved in modulating this process remains largely unknown.

Methods

We first analyzed the expression of SUMO1 in airway epithelial tissues from asthmatic patients and its correlation with the expression of tight junction molecules (ZO-1, Occludin, Claudin-1). Next, an in vitro model of epithelial barrier disruption was established by stimulating airway epithelial cells with endogenous/exogenous stimuli (house dust mite, HDM; and IL-13), followed by detection of SUMO1 expression and histone SUMOylation levels. We then investigated the effects of inhibiting global SUMOylation or enhancing histone SUMOylation on epithelial barrier function in vitro. Finally, an in vivo murine model of asthma was employed to evaluate the impacts of SUMOylation inhibition on airway inflammation and epithelial barrier integrity.

Results

SUMO1 expression was significantly upregulated in airway epithelial tissues of asthmatic patients, and a prominent negative correlation was observed between SUMO1 and ZO-1 expression. Stimulation with HDM or IL-13 markedly enhanced histone H3 SUMOylation in airway epithelial cells. Functionally, inhibition of SUMOylation significantly ameliorated epithelial barrier function while upregulating ZO-1 expression. Conversely, overexpression of H3-SUMO1 via plasmid transfection significantly suppressed ZO-1 expression and impaired airway epithelial barrier function. In asthmatic mice, administration of a SUMOylation inhibitor effectively alleviated airway inflammation, airway hyperresponsiveness, and epithelial barrier disruption.

Conclusions

In summary, our study confirms that inhibition of histone H3 SUMOylation improves airway epithelial barrier function in asthma, highlighting the potential of targeting histone SUMOylation for asthma treatment.

This abstract is funded by: National Natural Science Foundation of China (82300032),Guangzhou Basic and Applied Basic Research Scheme (2024A04J3311)