scholarly journals Effects of Shikonin on the Functions of Myeloid Dendritic Cells in a Mouse Model of Severe Aplastic Anemia

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Mengying Zheng ◽  
Bingnan Liu ◽  
Yuanyuan Shao ◽  
Luogang Hua ◽  
Rong Fu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mouse Model ◽  
Cyclosporin A ◽  
Aplastic Anemia ◽  
Survival Rates ◽  
Severe Aplastic Anemia ◽  
High Survival ◽  
Myeloid Dendritic Cells ◽  
Cd8 Cells

This study is aimed at investigating the effects of shikonin, a pyruvate kinase M2 (PKM2) inhibitor, on the functions of myeloid dendritic cells (mDCs) in a mouse model of severe aplastic anemia (AA) generated by total body irradiation and lymphocyte infusion. Flow cytometry and qPCR were used to determine the proportions of PKM2+ mDCs and other immune indicators in the AA mice. Glucose consumption level, pyruvate generation level, and ATP content were used to determine the level of glycolytic metabolism in the mDCs. The survival rates of AA mice were evaluated after the administration of shikonin or the immunosuppressive agent cyclosporin A. The AA mice displayed pancytopenia, decreased CD4+/CD8+ cell ratio, increased perforin and granzyme levels in CD8+ cells, increased costimulatory CD80 and CD86 expressions, and inadequate regulatory T cell number. In vivo animal experiments showed that the shikonin-mediated inhibition of the PKM2 expression in mice was associated with high survival rates. In addition, the administration of cyclosporin A or shikonin decreased the expression of cytotoxic molecules and costimulatory CD80 and CD86 on CD8+ cells. Taken together, the results of this study indicated that shikonin could inhibit the activation and proliferation of mDCs as well as the activation of downstream cytotoxic T cells by reducing the PKM2 level in mDCs.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Chunyan Liu ◽  
Mengying Zheng ◽  
Ting Wang ◽  
Huijuan Jiang ◽  
Rong Fu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Immune Status ◽  
Bone Marrow Failure ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells ◽  
Protein Levels ◽  
Immune Mediated ◽  
Normal Controls

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.

Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia

2011 ◽  
Vol 93 (2) ◽  
pp. 156-162 ◽  
Author(s):  
Shao Zonghong ◽  
Tu Meifeng ◽  
Wang Huaquan ◽  
Xing Limin ◽  
Wang Jun ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells

Severe aplastic anemia (SAA): Response to cyclosporin A (CyA) in vivo and in vitro

2009 ◽  
Vol 46 (4) ◽  
pp. 212-216 ◽  
Author(s):  
J. Tong ◽  
A. Bacigalupo ◽  
G. Piaggio ◽  
O. Figari ◽  
M. T. Lint ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia

scholarly journals The Effect of Pyruvate Kinase M2: Inhibitor(shikonin) on the Function of Mdc in Severe Aplastic Anemia Mouse Model

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5021-5021
Author(s):  
Mengying Zheng ◽  
Chunyan Liu ◽  
Yuanyuan Shao ◽  
Rong Fu ◽  
Huaquan Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Aplastic Anemia ◽  
Pyruvate Kinase ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Autoimmune Response ◽  
Severe Aplastic Anemia ◽  
Pyruvate Kinase M2 ◽  
Cd8 Cells ◽  
Cytotoxic Molecules

Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Over-activated myeloid dendritic cells (mDCs) play an important role in the pathogenesis of SAA. In recent years, the role of pyruvate kinase M2 (PKM2) in DC function and autoimmune response has been gradually recognized. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation and lymphocyte infusion. The AA model mice showed pancytopenia, decreased ratio of CD4+/CD8+ cells, increased expression of cytotoxic molecules perforin and granzyme in CD8+ cells, increased levels of co-stimulatory molecules CD80 and CD86 in DCs and inadequate Treg number. In-vitro animal experiments confirmed the activation of PKM2 in mDCs, which promoted glycolytic metabolism. High levels of PKM2 in mice contributed to the poor survival rate. Additionally, intervention treatment with shikonin or cyclosporin A in the AA mouse model reduced the expression not only of co-stimulatory molecules CD80 and CD86 in mDCs but also of cytotoxic molecules in CD8+ cells. In conclusion, we confirmed the activation of PKM2 in mDCs in AA mouse models. PKM2 is involved in mDC activation and proliferation, which might contribute to activating the downstream cytotoxic T cells (CTLs). PKM2 is a possible novel target in SAA treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Upregulated Expression of Profilin1 on Dendritic Cells in Patients With Severe Aplastic Anemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Hong Yu ◽  
Yang Zhao ◽  
Xiaofeng Pan ◽  
Chunyan Liu ◽  
Rong Fu
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Cell Movement ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells ◽  
Life Threatening ◽  
Movement Ability ◽  
Antigen Presenting

Severe aplastic anemia (SAA) is a life-threatening form of bone marrow failure that is associated with very high mortality. Dendritic cells (DCs) are antigen presenting cells (APCs) with powerful movement ability, which is an important factor affecting immune function. The expression of profilin1 (Pfn1) plays an important role in the regulation of cell movement ability. We detected the expression of Pfn1 mRNA in the bone marrow (BM) myeloid dendritic cells (mDCs) from patients with SAA using RT-PCR. Next, we examined Pfn1 expression on mDCs using flow cytometry (FCM). We also assessed the relationship between Pfn1 expression and cytokine levels. Our data showed increased Pfn1 mRNA expression in patients with SAA. The expression of Pfn1 in BM mDCs increased in SAA patients. The expression of Pfn1 on mDCs and cytokines (TNF-α and IFN-γ) were positively correlated in the serum of untreated patients with SAA. Taken together, we found that the expression of Pfn1 on mDCs of SAA patients increased, which may affect the function of mDCs. Profilin 1 may be involved in the immunopathogenesis of SAA.

Changes of Subsets of DC 1 in the Bone Marrow of Severe Aplastic Anemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3712-3712
Author(s):  
Guangsheng He ◽  
Zhonghong Shao ◽  
De Pei Wu ◽  
Xiao Ma ◽  
Aining Sun
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Aplastic Anemia ◽  
Severe Aplastic Anemia ◽  
Stable Form ◽  
Th1 Cells ◽  
Th1 Cell ◽  
Cd8 Cells ◽  
Normal Controls

Abstract Objective To measure the changes of subsets of dendritic cells 1 (DC1) in the bone marrow of severe aplastic anemia (SAA) patients and evaluate the relationships between the CD11c+CD83+cells and Th1 cells, CD3+CD8+ cells or hematopoietic function. Methods By FACS, the quantity and ratio of CD11c+CD1a+ cells, CD11c+CD83+ cells, Th1 cells, and CD3+CD8+ cells in the bone marrow of SAA patients and normal controls were detected respectively. The relationships between CD3+CD8+ cells and Ret or ANC, between Th1 cells and CD3+CD8+ cells, Ret or ANC, between CD11c+CD83+ cells, and Th1 cells, CD3+CD8+ cells, Ret or ANC were evaluated. Results In normal control’s bone marrow, the percentages of Th1 cells, CD11c+CD1a+ cells, CD11c+CD83+ cells and ratio of CD11c+CD83+ /CD11c+CD1a+ was 0.42±0.30%, 0.38±0.29%, 0.37±0.32% and 1.07±0.10 respectively. In the untreated SAA patient’s bone marrow, they were 4.87±0.54%, 1.73±0.24%, 3.38±0.56% and 2.21±0.32 respectively, and increased markedly(p<0.01). In recovering SAA patient’s bone marrow, the percentages of Th1 cells, CD11c+CD1a+ cells and CD11c+CD83+ cells decreased significantly[0.53±0.22%, 0.61±0.23%, 0.65±0.22%, respectively (p<0.01)]. The ratio of CD11c+CD83+/CD11c+ CD1a+ of recovering SAA patients was 1.37±0.25 which was similar to that of normal controls (p>0.05). The percentages of CD3+CD8+ cells of untreated SAA patients was 32.32±10.22%, and that of recovering SAA patients decreased to 13.67%±5.24 significantly (p<0.01). The percentages of CD3+CD8+ cells of SAA patients were correlated to their Ret and ANC (P<0.05) negatively. Their Th1 cell percentages were correlated to their CD3+CD8+ cells positively (P<0.01), but to their Ret and ANC negatively(p<0.01). SAA patient’s CD11c+CD83+ cell percentages were correlated to their Th1 cell and CD3+CD8+ cells positively (P<0.01, P<0.05), but to their Ret and ANC negatively(p<0.01). Conclusion Both immature DC1 and activated DC1 increased in the bone marrow of SAA patients, and the balance of subsets of DC1 shifted from stable form to active one, which might promote Th0 cells to polarize to Th1 cells, then cause the over-function of T lymphocytes and hematopoietic failure in SAA.

Differential expression of the proteome of myeloid dendritic cells in severe aplastic anemia

2013 ◽  
Vol 285 (1-2) ◽  
pp. 141-148 ◽  
Author(s):  
Chunyan Liu ◽  
Weiwei Sheng ◽  
Rong Fu ◽  
Huaquan Wang ◽  
Lijuan Li ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Aplastic Anemia ◽  
Differential Expression ◽  
Severe Aplastic Anemia ◽  
Myeloid Dendritic Cells

A novel mouse model based on intersectional genetics enables unambiguous in vivo discrimination between plasmacytoid and other dendritic cells and their comparative characterization

2022 ◽  
Author(s):  
Michael Valente ◽  
Nils Collinet ◽  
Thien-Phong Vu Manh ◽  
Karima Naciri ◽  
Gilles Bessou ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Steady State ◽  
Mouse Model ◽  
Single Cell ◽  
Ex Vivo ◽  
High Specificity ◽  
Type I ◽  
Specific Expression ◽  
Physiological Functions

Plasmacytoid dendritic cells (pDC) were identified about 20 years ago, based on their unique ability to rapidly produce copious amounts of all subsets of type I and type III interferon (IFN-I/III) upon virus sensing, while being refractory to infection. Yet, the identity and physiological functions of pDC are still a matter of debate, in a large part due to their lack of specific expression of any single cell surface marker or gene that would allow to track them in tissues and to target them in vivo with high specificity and penetrance. Indeed, recent studies showed that previous methods that were used to identify or deplete pDC also targeted other cell types, including pDC-like cells and transitional DC (tDC) that were proposed to be responsible for all the antigen presentation ability previously attributed to steady state pDC. Hence, improving our understanding of the nature and in vivo choreography of pDC physiological functions requires the development of novel tools to unambiguously identify and track these cells, including in comparison to pDC-like cells and tDC. Here, we report successful generation of a pDC-reporter mouse model, by using an intersectional genetic strategy based on the unique co-expression of Siglech and Pacsin1 in pDC. This pDC-Tomato mouse strain allows specific ex vivo and in situ detection of pDC. Breeding them with Zbtb46GFP mice allowed side-by-side purification and transcriptional profiling by single cell RNA sequencing of bona fide pDC, pDC-like cells and tDC, in comparison to type 1 and 2 conventional DC (cDC1 and cDC2), both at steady state and during a viral infection, revealing diverging activation patterns of pDC-like cells and tDC. Finally, by breeding pDC-Tomato mice with Ifnb1EYFP mice, we determined the choreography of pDC recruitment to the micro-anatomical sites of viral replication in the spleen, with initially similar but later divergent behaviors of the pDC that engaged or not into IFN-I production. Our novel pDC-Tomato mouse model, and newly identified gene modules specific to combinations of DC types and activations states, will constitute valuable resources for a deeper understanding of the functional division of labor between DC types and its molecular regulation at homeostasis and during viral infections.

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