Accumulation of myeloid-derived suppressor cells (MDSCs) is one of the major obstacles against achieving appropriate anti-tumor immune responses and successful tumor immunotherapy. Granulocytic MDSCs (G-MDSCs) are common in tumor-bearing hosts. However, the mechanisms regulating the development of MDSCs, especially G-MDSCs, remain poorly understood. In this report, we showed that interferon regulatory factor 7 (IRF7) plays an important role in the development of G-MDSCs, but not monocytic MDSCs. IRF7 deficiency caused significant elevation of G-MDSCs, and therefore enhanced tumor growth and metastasis in mice. IRF7 deletion did not affect the suppressive activity of G-MDSCs. Mechanistic studies showed that S100A9, a negative regulator of myeloid cell differentiation, was transrepressed by the IRF7 protein. S100A9 knockdown almost completely abrogated the effects of IRF7 deletion on G-MDSC development and tumor metastasis. Importantly, IRF7 expression levels negatively correlated with the G-MDSC frequency and tumor metastasis, as well as S100A9 expression, in cancer patients. In summary, our study demonstrated that IRF7 represents a novel regulator of G-MDSC development in cancer, which may have predictive value for tumor progression.
c L-Arginine and L-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colonystimulating factor culture system and also facilitated the differentiation of CD8␣ ؉ conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation. Dendritic cells (DCs) are specialized antigen-presenting cells that capture, process, and present antigens to T cells and thereby play important roles in both innate and adaptive immunity (1, 2). Differentiation of DCs from hematopoietic progenitor cells (HPCs) is regulated by complex signaling pathways that involve soluble cytokines and transcription factors (TFs) in bone marrow (BM) and peripheral lymphoid tissues (3, 4). Impaired DC differentiation facilitates the escape of tumor cells and invading pathogens from the host's immune surveillance (5-7). Although many molecular mechanisms linked to DC differentiation have been proposed, a complete picture has yet to be obtained (8-10).L-Arginine is a conditionally essential amino acid in adult mammals because it is required under some special circumstances such as trauma, pregnancy, and infections. L-Arginine is metabolized by arginase (Arg) to produce urea and L-ornithine and by nitric oxide synthase to produce nitric oxide and L-citrulline. There are two known Arg isoforms, Arg1 and Arg2. Arg1 is constitutively expressed in the liver, where it participates in the urea cycle, while Arg2 is located in mitochondria in various cell types (11). Recently, it was reported that Arg1 expression is induced in myeloid cells exposed to Th2 cytokines such as interleukin-4 (IL-4) and IL-13. Induction of Arg1 or Nos2 has been used to distinguish macrophages activated through either the classical or the alternative pathway (12). Upregulation of Arg1 and Nos2 is closely associated with the suppressive activity of myeloid-derived suppressor cel...
Increased numbers of myeloid-derived suppressor cells (MDSCs) are often observed in various pathological and physiological conditions. However, the interactions between neurotransmitters and MDSCs have not been elucidated. In this study, we studied whether norepinephrine (NE), a neurotransmitter, could affect the differentiation of human MDSCs in vitro. Flow cytometric analysis showed that treatment with 20 μM NE significantly enhanced the expansion of MDSCs. The NE-generated MDSCs suppressed the T-cells proliferation, depending on the production of reactive oxygen species (ROS). Moreover, the expansion of MDSCs induced by NE resulted in a dramatic induction of nicotinamide adenine dinucleotide phosphate oxidase subunit P47(phox). Addition of the ROS inhibitor catalase into the MDSCs/T-cell co-culture system partly abrogated the suppressive effects of MDSCs on T-cell proliferation. In summary, our data have shown that NE enhanced the expansion of human MDSCs in vitro, providing important insights into the novel roles of neurotransmitters in the regulation of myeloid cell differentiation and function.
Glucocorticoids (GCs) used as inflammation suppressors have harmful side effects, including induction of hepatic steatosis. The underlying mechanisms of GC-promoted dysregulation of lipid metabolism, however, are not fully understood. GCs could facilitate the accumulation of myeloid-derived suppressor cells (MDSC) in the liver of animals, and the potential role of MDSCs in GC-induced hepatic steatosis was therefore investigated in this study. We demonstrated that granulocytic (G)-MDSC accumulation mediated the effects of GCs on the fatty liver, in which activating transcription factor 3 (ATF3)/S100A9 signaling plays an important role. ATF3-deficient mice developed hepatic steatosis and displayed expansion of G-MDSCs in the liver and multiple immune organs, which shared high similarity with the phenotype observed in GC-treated wild-type littermates. Adoptive transfer of GC-induced or ATF3-deficient G-MDSCs promoted lipid accumulation in the liver, whereas depletion of G-MDSCs alleviated these effects. Mechanistic studies showed that in MDSCs, ATF3 was transrepressed by the GC receptor GR through direct binding to the negative GR-response element. S100A9 is the major transcriptional target of ATF3 in G-MDSCs. Silencing S100A9 clearly alleviated G-MDSCs expansion and hepatic steatosis caused by ATF3 deficiency or GC treatment. Our study uncovers an important role of G-MDSCs in GC-induced hepatic steatosis, in which ATF3 may have potential therapeutic implications.
Background: Manual microscopic examination is the gold standard of humoral cell count test. However, it has some limitations and cannot fully meet clinical needs. Compared with the manual method, the automatic blood cell analyzer has the advantages of a high degree of automation, minimal error, high speed, high precision, and easy standardization. This study intends to verify the detection performance of the body fluid model of the Mindray BC-6000PLUS automatic hematology analyzer. Methods: This study was performed in accordance with the International Committee for Standardization in Haematology (ICSH) Hematology Analyzer Evaluation Guide (version 2014) and the requirements of WS/T662-2020 "Clinical humoral examination technique". The humoral white blood cell-body fluid (WBC-BF), humoral red blood cell-body fluid (RBC-BF), monocyte (MN), polymorphonuclear (PMN)were measured to verify the performance indicators of the instrument, including background counting, intrabatch precision, accuracy, carrying contamination rate, and linear range. Referring to the WS/T514-2017 (Establishment and verification of detection capability for clinical laboratory measurement procedures), the limit of blank (LoB) and limit of detection (LoD) values of WBC-BF and RBC-BF in the humoral mode of the instrument were established. Results:The blank count of WBC-BF and RBC-BF, and contamination of Mindray BC-6000PLUS analyzer were zero; the coefficient of variation (CV) of intra-batch precision at different levels of each item was less than 10%. There was a high correlation between instrument test results and manual microscopic examination results (r>0.95). The linear range of the instrument was wide, and the linear verification parameters was good (R²>0.
Elevation of myeloid-derived suppressor cells (MDSCs) was observed in some viral infectious diseases. In this study, we studied whether ribavirin, a widely used clinical antiviral drug, could impact the differentiation of human MDSCs in vitro. Flow cytometric analysis showed that ribavirin treatment (5-20 µg/ml) significantly enhanced the differentiation of monocytic MDSCs in a dose-dependent manner. The ribavirin-generated MDSCs were immune-suppressive toward autologous T cells. The mRNA expression of some cytokines was further examined by quantitative reverse transcription polymerase chain reaction. We observed a significant down-regulation of chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 mRNA in ribavirin-generated MDSCs, when compared with control. Peripheral blood mononuclear cells from clinical chronic hepatitis C patients subjected to ribavirin therapy also displayed a similar suppression in CXCL9/10 mRNA expression. Administration of recombinant CXCL9/10 proteins clearly counteracted the effect of ribavirin on MDSCs. In summary, this study showed that ribavirin enhanced human MDSCs differentiation in vitro, which may be attribute to the down-regulation of CXCL9/10 expression.
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