The mobilization of splenic reservoir myeloid-derived suppressor cells in sepsis-induced myocardial injury

Cong Fu; Qiancheng Xu; Shengxing Tang; Yuhan Cao; Can Liu; Yihua Wang; Yan Qian; Fei Shi; Jingmin Gui; Qun Fan; Yang Ling

The mobilization of splenic reservoir myeloid-derived suppressor cells in sepsis-induced myocardial injury

Am J Transl Res. 2020 Nov 15;12(11):7114-7126. eCollection 2020.

Authors

Cong Fu¹, Qiancheng Xu², Shengxing Tang¹, Yuhan Cao³, Can Liu⁴, Yihua Wang⁵, Yan Qian⁶, Fei Shi⁷, Jingmin Gui⁸, Qun Fan¹, Yang Ling¹

Affiliations

¹ Department of Cardiology, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College Wuhu, Anhui, China.
² Department of Critical Care Medicine, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College Wuhu, Anhui, China.
³ Department of Nephrology, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College Wuhu, Anhui, China.
⁴ Department of Anesthesiology, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College Wuhu, Anhui, China.
⁵ Department of Emergency Intensive Care Unit, Yi Ji Shan Hospital Affiliated to Wan Nan Medical College Wuhu, Anhui, China.
⁶ Department of Critical Care Medicine, The Second People's Hospital of Wuhu Wuhu, Anhui, China.
⁷ Department of Critical Care Medicine, Wuhu Hospital for Traditional Chinese Medicine Wuhu, Anhui, China.
⁸ Department of Critical Care Medicine, The First People's Hospital of Wuhu Wuhu, Anhui, China.

PMID: 33312354
PMCID: PMC7724347

Abstract

Background: Myeloid-derived suppressor cells (MDSCs) play key roles in sepsis, but whether the bone marrow is considered the only source remains unclear. The current knowledge about the mechanism of MDSCs leading to myocardial injury in sepsis is poor.

Methods: In sepsis patients with cardiac dysfunction, the circulating percentage of CD14^-CD11b⁺ and serum concentrations of IL-6 and IL-1β were measured. A mouse sepsis model was established through caecum ligation and puncture (CLP). Animals were divided into four groups: control, sham, CLP and CLP+splenectomy (CLPS). Serum concentrations of IL-6, IL-1β, TnI and NT-proBNP were measured. CD11b⁺Gr-1⁺ cells were detected by immunofluorescence staining and RT-PCR. Myocardial injury was detected by HE, Masson and TUNEL staining. The expression of mTOR, P53 and caspase-3 was measured by Western blot.

Results: In sepsis patients, circulating MDSCs were increased, and the serum concentrations of IL-6 and IL-1β were elevated. The serum concentrations of IL-6 and IL-1β were correlated with the ratio of circulating MDSCs. In the mouse sepsis model, the spleen was the major source of CD11b⁺Gr-1⁺ cells that migrated into circulation and the heart in sepsis. The serum concentrations of IL-6 and IL-1β were also elevated. Echocardiography and serum biomarkers showed that cardiomyocyte damage and cardiac hypofunction in sepsis-induced myocardial injury. The expression of CD11b, Gr-1 and pro-inflammatory cytokines in the heart was significantly higher in sepsis patients than that in controls. Pathological staining and TUNEL staining showed obvious myocardial damage and cell apoptosis. The Western blot analysis indicated that in the heart, the activation of mTOR was inhibited and that the expression of P53 and caspase-3 was elevated in sepsis-induced myocardial injury.

Conclusion: In sepsis-induced myocardial injury, splenic reservoir CD11b⁺Gr-1⁺ cells rapidly migrated into circulation and the heart, further impairing heart function via the high expression of P53 through the inhibition of mTOR.

Keywords: MDSCs; Sepsis; inflammation; mTOR; myocardial injury.