Impaired mitochondria of Tregs decreases OXPHOS-derived ATP in primary immune thrombocytopenia with positive plasma pathogens detected by metagenomic sequencing

Yanxia Zhan; Jingjing Cao; Lili Ji; Miaomiao Zhang; Qi Shen; Pengcheng Xu; Xibing Zhuang; Shanshan Qin; Fanli Hua; Lihua Sun; Feng Li; Hao Chen; Yunfeng Cheng

doi:10.1186/s40164-022-00304-y

Impaired mitochondria of Tregs decreases OXPHOS-derived ATP in primary immune thrombocytopenia with positive plasma pathogens detected by metagenomic sequencing

Exp Hematol Oncol. 2022 Sep 1;11(1):48. doi: 10.1186/s40164-022-00304-y.

Authors

Yanxia Zhan^#¹, Jingjing Cao^#¹, Lili Ji¹, Miaomiao Zhang², Qi Shen², Pengcheng Xu^{1

3}, Xibing Zhuang^{1

3}, Shanshan Qin^{1

2}, Fanli Hua⁴, Lihua Sun⁴, Feng Li^{1

4}, Hao Chen⁵, Yunfeng Cheng^{6

7

8

9}

Affiliations

¹ Department of Hematology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China.
² Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
³ Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China.
⁴ Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China.
⁵ Department of Thoracic Surgery, Zhongshan Hospital Xuhui Branch, Fudan University, 966 Mid Huaihai Rd, Shanghai, 200031, China. h.chen@fudan.edu.cn.
⁶ Department of Hematology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. yfcheng@fudan.edu.cn.
⁷ Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. yfcheng@fudan.edu.cn.
⁸ Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China. yfcheng@fudan.edu.cn.
⁹ Department of Hematology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai, 201700, China. yfcheng@fudan.edu.cn.

^# Contributed equally.

Abstract

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease. Some ITP patients are associated with pathogen infection undetected with conventional technologies. Investigating the changes of T cells and potential metabolic mechanism are important for better understanding of ITP.

Methods: The study enrolled 75 newly diagnosed ITP patients. The pathogens of patients were detected by metagenomic next-generation sequencing (mNGS). Plasma lipids were measured by liquid chromatography-mass spectrometry (LC-MS). CD4 T cell and CD8 T cell were analyzed using flow cytometry. Mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential were measured by flow cytometry. Seahorse XF real-time ATP rate assay was used to investigate the change of cellular metabolism.

Results: Positive plasma pathogens were detected in seven ITP patients. Of them, 5 (71.4%) positive pathogen-ITP patients were no response (NR) after first-line treatment with corticosteroids. Regulatory T cells (Tregs) increased significantly in positive pathogen-ITP patients compared to negative pathogen-ITP patients and healthy controls (HC). Mitochondrial membrane potential of Th17 and Tregs were decreased in positive pathogen-ITP and negative pathogen-ITP patients, compared to HC (all p < 0.05). The overall metabolism flux of positive pathogen-ITP patients was decreased, as compared to HC (p = 0.004), of them a higher proportion of glycolysis-derived ATP and a smaller proportion of oxidative phosphorylation (OXPHOS)-derived ATP were found in Tregs. The ATP rate index of Tregs was decreased significantly in positive pathogen-ITP patients compared to negative pathogen-ITP patients and HC (p < 0.05).

Conclusions: Impaired mitochondria function of Tregs in positive pathogen-ITP patients caused a decrease of OXPHOS-derived ATP and overall metabolism flux that might be the cause of steroid resistance in ITP patients.

Keywords: Glycolysis; Immune thrombocytopenia; Oxidative phosphorylation; Pathogens; Tregs (Regulatory T cells).

Abstract

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