Abnormal acetylation of FOXP3 regulated by SIRT-1 induces Treg functional deficiency in patients with abdominal aortic aneurysms

Background and aims Acetylation levels of FOXP3 could influence its expression level and SIRT1 is a deacetylase, which could regulate the acetylation level of FOXP3. We aimed to investigate the mechanism of Treg dysfunction, which might be caused by abnormal acetylation of FOXP3 regulated by SIRT1 in abdominal aortic aneurysm (AAA) patients. Methods Peripheral CD4+ T cells from AAA patients, abdominal aortic atherosclerotic occlusive disease (AOD) patients, and healthy donors (HC) were analyzed by flow cytometry to determine the percentage of CD4+CD25+ Tregs and CD4+CD25+FOXP3+ T cells in CD4+ T cells. Expression of FOXP3 and SIRT1 was analyzed by Western Blot. Cultured CD4+ T cells were treated with SIRT1 specific inhibitor EX-527 or left untreated. Acetylation expression of FOXP3 in CD4+ T cells was analyzed by immunoprecipitation and Western Blot. The suppressive function of Treg was analyzed by CFSE-assay. Results AAA patients had significantly lower CD4+CD25+FOXP3+ T cells. Western blot results showed that AAA CD4+ T cells had significantly less FOXP3 expression but significantly higher SIRT1 expression. After EX-527 treatment, CD4+CD25+FOXP3+ T cells and FOXP3 expression in the AAA group were significantly increased. FOXP3 acetylation level in the AAA group was lower than in control groups. After EX-527 treatment, it was significantly increased. AAA Tregs exhibited less suppressive activity, EX-527 treatment significantly increased the suppressive activity of AAA Tregs. Conclusions Our data demonstrate that reduced FOXP3 expression and Treg function in AAA patients are regulated by SIRT1-induced FOXP3 deacetylation. EX-527 could up-regulate FOXP3 acetylation and increase number and suppressive function of Treg in AAA patients.