Han Jiang1, Shijie Xin1, Yumeng Yan2, Yu Lun1, Xiao Yang1, Jian Zhang3. 1. Department of Vascular Surgery, The First Hospital of China Medical University, Nanjing Bei Str. 155, Shenyang 110001, China. 2. Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Sanhao Str. 36, Shenyang 110004, China. 3. Department of Vascular Surgery, The First Hospital of China Medical University, Nanjing Bei Str. 155, Shenyang 110001, China. Electronic address: jianzhang@cmu.edu.cn.
Abstract
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.
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.
Authors: Song Lu; John V White; Raquel I Judy; Lisa L Merritt; Wan Lu Lin; Xiaoying Zhang; Charalambos Solomides; Ifeyinwa Nwaneshiudu; John Gaughan; Dimitri S Monos; Emilia L Oleszak; Chris D Platsoucas Journal: PLoS One Date: 2019-07-16 Impact factor: 3.240
Authors: Frank M Davis; Lam C Tsoi; William J Melvin; Aaron denDekker; Rachael Wasikowski; Amrita D Joshi; Sonya Wolf; Andrea T Obi; Allison C Billi; Xianying Xing; Christopher Audu; Bethany B Moore; Steven L Kunkel; Alan Daugherty; Hong S Lu; Johann E Gudjonsson; Katherine A Gallagher Journal: J Exp Med Date: 2021-06-07 Impact factor: 14.307