PKM2 Is Required to Activate Myeloid Dendritic Cells from Patients with Severe Aplastic Anemia.

Chunyan Liu,Zonghong Shao,Huaquan Wang,Huijuan Jiang,Mengying Zheng,Kai Ding,Ting Wang,Rong Fu,Qiufan Zhou

doi:10.1155/2018/1364165

Abstract

Severe aplastic anemia (SAA) is an autoimmune disease in which bone marrow failure is mediated by activated myeloid dendritic cells (mDCs) and T lymphocytes. Recent research has identified a strong immunomodulatory effect of pyruvate kinase M2 (PKM2) on dendritic cells in immune-mediated diseases. In this study, we aimed to explore the role of PKM2 in the activation of mDCs in SAA. We observed conspicuously higher levels of PKM2 in mDCs from SAA patients compared to normal controls at both the gene and protein levels. Concurrently, we unexpectedly discovered that after the mDC-specific downregulation of PKM2, mDCs from patients with SAA exhibited weakened phagocytic activity and significantly decreased and shortened dendrites relative to their counterparts from normal controls. The expression levels of the costimulatory molecules CD86 and CD80 were also reduced on mDCs. Our results also suggested that PKM2 knockdown in mDCs reduced the abilities of these cells to promote the activation of CD8+ T cells (CTLs), leading to the decreased secretion of cytotoxic factors by the latter cell type. These findings demonstrate that mDC activation requires an elevated intrinsic PKM2 level and that PKM2 improves the immune status of patients with SAA by enhancing the functions of mDCs and, consequently, CTLs.

Highlights

Severe aplastic anemia (SAA) is a hematologic disease characterized by pancytopenia with severe bone marrow failure
Elevated pyruvate kinase M2 (PKM2) mRNA and Protein Expression in Myeloid dendritic cells (mDCs) Cells from SAA Patients. Both western blotting and qPCR were used to evaluate the expression of PKM2 mRNA and protein in mDC cells from untreated SAA patients, patients in remission, and normal controls
SAA is characterized by severe pancytopenia and a bone marrow hematopoietic failure, with clinical symptoms including fatal anemia, infection, and bleeding

Summary

Introduction

Severe aplastic anemia (SAA) is a hematologic disease characterized by pancytopenia with severe bone marrow failure. An increasing number of studies have recognized SAA as an autoimmune disease in which bone marrow failure is mediated by activated T lymphocytes [1, 2]. Myeloid dendritic cells (mDCs) have recently been recognized as important players in the primary immune responses related to SAA. Our previous research demonstrated increases in both the immature and activated mDC populations in the bone marrow of SAA patients, indicating that immune imbalances might originate from an early stage in the antigen recognition process [3]. Knowledge about the immunopathogenesis of SAA has improved gradually after years of research, the specific mechanism by which activated mDCs and even T cells are involved requires further validation. The immune etiology of SAA has become the focus of further research

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