Myeloid-derived suppressor cells promote the formation of abdominal aortic aneurysms through the IL-3-ICOSL-ICOS axis
Li Lu,
Yi Jin,
Yuanhao Tong,
Lun Xiao,
Yayi Hou,
Zhao Liu,
Huan Dou
Affiliations
Li Lu
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China
Yi Jin
Department of Vascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
Yuanhao Tong
Department of Vascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
Lun Xiao
Department of Vascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China
Yayi Hou
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China; Corresponding authors at: H. Dou, Y. Hou, The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu, Jiangsu Key Laboratory of Molecular Medicine, No. 22 Hankou Rd, Nanjing, 210093, China.
Zhao Liu
Department of Vascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, China; Corresponding author at: Z. Liu, Department of Vascular Surgery, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, No. 321 Zhongshan Road, Nanjing, 210008, China.
Huan Dou
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China; Corresponding authors at: H. Dou, Y. Hou, The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu, Jiangsu Key Laboratory of Molecular Medicine, No. 22 Hankou Rd, Nanjing, 210093, China.
Th17 cells are powerful inflammation promoters in the pathogenesis of abdominal aortic aneurysms (AAAs). Myeloid-derived suppressor cells (MDSCs) can promote the differentiation of Th17 cells in chronic inflammatory autoimmune injury. Here, we aim to examine whether MDSCs regulate the differentiation of Th17 cells to participate in the development of AAA. We demonstrated an abnormal accumulation of MDSCs in AAA patients, which was positively associated with Th17 cells. We established angiotensin II-induced apolipoprotein E knockout mice and found the impaired immunosuppressive function of M-MDSCs. After systemic injection of anti-Gr-1 antibody in AAA mice to deplete circulating MDSCs, AAA formation and the differentiation of Th17 cells were abolished, and the overexpression of inducible T-cell costimulator (ICOS) on Th17 cells was reversed accordingly. Regulating the expression of ICOS ligand (ICOSL) on MDSCs affects the differentiation of Th17 cells. The adoptive transfer of ICOSLlowMDSCs in AAA mice inhibited the differentiation of Th17 cells and the development of AAA. Meanwhile, rIL-3 promoted the survival and immunosuppressive dysfunction of MDSCs, upregulated ICOSL expression on MDSCs by inhibiting activation of the PI3K/AKT signaling pathway, and regulated MDSCs to promote the differentiation of Th17 cells via the ICOSL-ICOS axis. An increase in serum IL-3, ICOSL+MDSCs, and ICOS+Th17 cells was detected in AAA patients, and IL-3 levels were positively correlated with the proportion of ICOSL+MDSC cells. In conclusion, we uncovered a pivotal role of MDSCs in promoting the differentiation of Th17 cells through the IL-3-ICOSL-ICOS axis during AAA, providing an important theoretical basis for understanding the pathogenesis of AAA.
