Jiahui Fan, Kun Miao, Chunxia Zhao, Jing Wang, Zunyue Zhang, Huaping Li, Zhuoya Li, Fang Chen, Hongping Ba, Ling Zhou, Bingjiao Yin, Yazhen Zhu, Dao Wen Wang
Background -Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand in cancer, inflammation, and infection and negatively regulate inflammation and the immune response. Heart failure (HF) is a complex clinical syndrome, wherein inflammation induction and incomplete resolution can potentially contribute to HF development and progression. However, the role of MDSCs in HF remains unclear. Methods -The percentage of MDSCs in HF patients and in mice with pressure overload-induced HF using isoproterenol (ISO) infusion or transverse aortic constriction (TAC), was detected by flow cytometry. The effects of MDSCs on ISO- or TAC-induced HF were observed upon depleting MDSCs with 5-fluorouracil (50 mg/kg) or gemcitabine (120 mg/kg), transferring purified MDSCs, or enhancing endogenous MDSCs with rapamycin (2 mg/kg/day). Hypertrophic markers and inflammatory factors were detected by enzyme-linked immunosorbent assay, real-time polymerase chain reaction, or western blot. Cardiac functions were determined by echocardiography and hemodynamic analysis. Results -The percentage of human leukocyte antigen-D-related (HLA-DR)-CD33+CD11b+ MDSCs in the blood of HF patients was significantly increased and positively correlated with the disease severity and increased plasma levels of cytokines, including interleukin (IL)-6, IL-10, and transforming growth factor-β. Furthermore, HF patient-derived MDSCs inhibited T-cell proliferation and interferon-γ secretion. Similar results were observed in TAC- and ISO-induced HF in mice. Importantly, pharmaceutical depletion of MDSCs significantly exacerbated ISO- and TAC-induced pathological cardiac remodeling and inflammation, whereas adoptive transfer of MDSCs prominently rescued ISO- and TAC-induced HF. Consistently, administration of rapamycin significantly increased endogenous MDSCs by suppressing their differentiation and improved ISO- and TAC-induced HF, but MDSC depletion mostly blocked beneficial rapamycin-mediated effects. Mechanistically, MDSC-secreted molecules suppressed ISO-induced hypertrophy and proinflammatory genes expression in cardiomyocytes in a co-culture system. Neutralization of IL-10 blunted both monocytic MDSC (M-MDSC)- and granulocytic MDSC (G-MDSC)-mediated anti-inflammatory and antihypertrophic effects, but treatment with a nitric oxide (NO) inhibitor only partially blocked the antihypertrophic effect of M-MDSCs. Conclusions -Our findings revealed a cardioprotective role of MDSCs in HF by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through IL-10 and NO. Pharmacological targeting of MDSCs by rapamycin constitutes a promising therapeutic strategy for HF.
