Abstract Background A growing number of studies have shown that the macrolide antibiotics have important and potential value in the treatment of chronic airway diseases for their non-anti-infective effects, such as powerful immunomodulatory properties. Our previous research has revealed that erythromycin treatment reduces exacerbations in patients with COPD. However, the underlying mechanism remains largely unknown. SUMOylation modifications are involved in the occurrence and development of chronic airway diseases. This study aimed to explore the role of SUMOylation in COPD and investigate whether erythromycin could ameliorate the pulmonary inflammation by modulating this pathway. Methods Expressions of SUMO1 were evaluated in clinical specimens by western blot and immunohistochemistry. Bioinformatic analyses were performed to evaluate the expressions of SUMOylation E3 ligases and deSUMOylation enzymes in COPD patients. Cigarette smoke extract (CSE) -induced PMA-differentiated THP-1 cell and mice exposed by cigarette smoke were established to explore the molecular mechanisms involved pulmonary inflammation induced by cigarette smoke. Results SUMO1 expression was significantly increased in COPD patients’ PBMCs and lung tissues. Bioinformatics analysis identified disorders of SUMOylation and deSUMOylation status in COPD. SENP1 was down-regulated in COPD patients’ PBMCs and lung tissues. Additionally, SENP1 down-regulation was confirmed in cigarette-induced PMA-differentiated THP1 cells as well as mice exposed by cigarette smoke. Pharmacological inhibition of SENP1 contributed to NFKB activation and pro-inflammatory cytokine production. Erythromycin was found to suppress the expression of SUMO1 and restore SENP1 expression in cigarette-induced THP1 cell. Moreover, erythromycin was confirmed to bind SENP1 through molecular docking, CETSA, DARTS and SPR. Additionally, BioGRID database analysis, molecular docking and GST-pull down revealed that SENP1 interacted with HDAC2. Co-IP assays and immunofluorescence demonstrated that erythromycin promoted the SENP1-HDAC2 interaction. Knockdown of SENP1 promoted HDAC2 SUMOylation and subsequent proteasomal degradation. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) identified the SUMOylation sites of HDAC2 in CSE induced PMA-differentiated THP-1 cell at K343. Mechanistically, down-regulation of SENP1 in CSE -induced PMA-differentiated THP-1 cell lead to HDAC2 SUMOylation and proteasomal degradation that promotes pro-inflammatory cytokine production. Conclusion Our study shows that erythromycin effectively alleviates cigarette smoke induced pulmonary inflammation induced by targeting SENP1 to de-SUMOylate HDAC2. This abstract is funded by: the National Natural Sci ence Foundation of China (No. 82260012).
He et al. (Fri,) studied this question.