scholarly journals LncRNA HOTAIRM1 promotes MDSC expansion and suppressive functions through the HOXA1-miR124 axis during HCV infection

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Bal Krishna Chand Thakuri ◽  
Jinyu Zhang ◽  
Juan Zhao ◽  
Lam N. Nguyen ◽  
Lam N. T. Nguyen ◽  
...  
Keyword(s):  
Viral Infection ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Hiv Infections ◽  
Arginase 1 ◽  
Non Coding Rna ◽  
Immature Myeloid Cells ◽  
Oxide Synthase ◽  
Long Non Coding Rna

AbstractHOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1 gene expression. We and others have previously shown that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells, expand during chronic viral (HCV, HIV) infections. However, the role of HOTAIRM1 in the development and suppression of MDSCs during viral infection remains unknown. In this study, we demonstrate that the expressions of HOTAIRM1 and its target HOXA1 are substantially upregulated to promote the expressions of immunosuppressive molecules, including arginase 1, inducible nitric oxide synthase, signal transducer and activator of transcription 3, and reactive oxygen species, in CD33+ myeloid cells derived from hepatitis C virus (HCV)-infected patients. We show that HCV-associated exosomes (HCV-Exo) can modulate HOTAIRM1, HOXA1, and miR124 expressions to regulate MDSC development. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy CD33+ myeloid cells promoted the MDSC differentiation and suppressive functions; conversely, silencing of HOTAIRM1 or HOXA1 expression in MDSCs from HCV patients significantly reduced the MDSC frequency and their suppressive functions. In essence, these results indicate that the HOTAIRM1-HOXA1-miR124 axis enhances the differentiation and suppressive functions of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.

scholarly journals HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3–miR124 Axis

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2715
Author(s):  
Bal Krishna Chand Thakuri ◽  
Jinyu Zhang ◽  
Juan Zhao ◽  
Lam N. Nguyen ◽  
Lam N. T. Nguyen ◽  
...  
Keyword(s):  
Viral Infections ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Hcv Infection ◽  
Host Immune Responses ◽  
Arginase 1 ◽  
Non Coding Rna ◽  
Related Transcription Factor ◽  
Chronic Hcv ◽  
Oxide Synthase

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR–RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33+ myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33+ myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR–RUNX1–STAT3–miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.

scholarly journals KDM6A Lysine Demethylase Directs Epigenetic Polarity of MDSCs during Murine Sepsis

2021 ◽  
pp. 1-12
Author(s):  
Isatou Bah ◽  
Tuqa Alkhateeb ◽  
Dima Youssef ◽  
Zhi Q. Yao ◽  
Charles E. McCall ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Transcription Activation ◽  
Myeloid Derived Suppressor Cells ◽  
Molecular Processes ◽  
Epigenetic Switch ◽  
Translation Research ◽  
Non Coding Rna ◽  
Genetic Deletion ◽  
Lysine Demethylase ◽  
Long Non Coding Rna

Sepsis-induced myeloid-derived suppressor cells (MDSCs) increase mortality risk. We previously identified that long non-coding RNA Hotairm1 supports myeloid precursor shifts to Gr1<sup>+</sup>CD11b<sup>+</sup> MDSCs during mouse sepsis. A major unanswered question is what molecular processes control Hotairm1 expression. In this study, we found by a genetic deletion that a specific PU.1-binding site is indispensable in controlling Hotairm1 transcription. We then identified H3K4me3 and H3K27me3 at the PU.1 site on the Hotairm1 promoter. Controlling an epigenetic switch of Hotairm1 transcription by PU.1 was histone KDM6A demethylase for H3K27me3 that derepressed its transcription with possible contributions from Ezh2 methyltransferase for H3K27me3. KDM6A knockdown in MDSCs increased H3K27me3, decreased H3K4me3, and inhibited Hotairm1 transcription activation by PU.1. These results enlighten clinical translation research of PU.1 epigenetic regulation as a potential sepsis immune-checkpoint treatment site.

Abstract 375: The Intergenic Long Non-Coding RNA RP11-472n13.3 Modulates Interferon-Gamma Signaling and M1 Macrophage Activation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ying Wang ◽  
Chenyi Xue ◽  
Muredach Reilly ◽  
Hanrui Zhang
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Induced Pluripotent Stem Cell ◽  
Myeloid Cell ◽  
Human Monocyte ◽  
Human Macrophage ◽  
Nucleotide Polymorphisms ◽  
Non Coding Rna ◽  
M1 Macrophage ◽  
Long Non Coding Rna

We aim to interrogate the functions of a subset of human macrophage intergenic long non-coding RNA (lincRNAs) which harbor cardiometabolic trait-associated single nucleotide polymorphisms (SNPs). We have found that one lincRNA RP11-472N13.3 overlaps rs7081678, a SNP significantly associated with central obesity (WHRadjBMI; P =5.57x10 -6 ). RP11-472N13.3 expression is enriched in macrophages relative to other obesity relevant tissues. Thus, RP11-472N13.3 SNPs for obesity may act via its myeloid cell modulation in adipose. In human monocyte-derived macrophage (HMDM), human induced pluripotent stem cell-derived macrophages (IPSDM) and THP1-derived macrophages (THP-1Φ), at RNAseq and Q-PCR, RP11-472N13.3 is abundant in M0 and M2(IL-4) macrophages but markedly suppressed in the M1 state (LPS/IFNγ). RP11-472N13.3 localizes almost exclusively to the cytoplasmic fraction of M0-HMDM. Consistent with GENCODE, our HMDM RNAseq data suggest a single 2-exon isoform. ChIP-seq reveals PU.1 and C/EBP-β binding at RP11-472N13.3 transcription start site. In our HMDM RNAseq (n=30 subjects) data, RP11-472N13.3 expression was inversely correlated with IFNγ-JAK-STAT signaling genes (e.g., IRF4, IL-12A, IL-23, STAT1, SOCS1, SOCS3 ), but not LPS/TLR4 activated genes (e.g., TNFA, CXCL9, CXCL10, IL1B ). Furthermore, KD of RP11-472N13.3 using siRNA or LNA-ASO in THP-1Φ, amplified expression of IFNγ target genes but not LPS/TLR4 targets during M1 activation (LPS/IFNγ). These data suggest its potential role in modulating IFNγ signaling. Mechanistic studies are needed to examine the molecular mechanisms.

scholarly journals Targeted deletion of PD-1 in myeloid cells induces antitumor immunity

2020 ◽  
Vol 5 (43) ◽  
pp. eaay1863 ◽  
Author(s):  
Laura Strauss ◽  
Mohamed A. A. Mahmoud ◽  
Jessica D. Weaver ◽  
Natalia M. Tijaro-Ovalle ◽  
Anthos Christofides ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Immunity ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effector Memory ◽  
Emergency Myelopoiesis

PD-1, a T cell checkpoint receptor and target of cancer immunotherapy, is also expressed on myeloid cells. The role of myeloid-specific versus T cell–specific PD-1 ablation on antitumor immunity has remained unclear because most studies have used either PD-1–blocking antibodies or complete PD-1 KO mice. We generated a conditional allele, which allowed myeloid-specific (PD-1f/fLysMcre) or T cell–specific (PD-1f/fCD4cre) targeting of Pdcd1 gene. Compared with T cell–specific PD-1 ablation, myeloid cell–specific PD-1 ablation more effectively decreased tumor growth. We found that granulocyte/macrophage progenitors (GMPs), which accumulate during cancer-driven emergency myelopoiesis and give rise to myeloid-derived suppressor cells (MDSCs), express PD-1. In tumor-bearing PD-1f/fLysMcre but not PD-1f/fCD4cre mice, accumulation of GMP and MDSC was prevented, whereas systemic output of effector myeloid cells was increased. Myeloid cell–specific PD-1 ablation induced an increase of T effector memory cells with improved functionality and mediated antitumor protection despite preserved PD-1 expression in T cells. In PD-1–deficient myeloid progenitors, growth factors driving emergency myelopoiesis induced increased metabolic intermediates of glycolysis, pentose phosphate pathway, and TCA cycle but, most prominently, elevated cholesterol. Because cholesterol is required for differentiation of inflammatory macrophages and DC and promotes antigen-presenting function, our findings indicate that metabolic reprogramming of emergency myelopoiesis and differentiation of effector myeloid cells might be a key mechanism of antitumor immunity mediated by PD-1 blockade.

scholarly journals Interleukin 1α (IL-1α) Promotes Pathogenic Immature Myeloid Cells and IL-1β Favors Protective Mature Myeloid Cells During Acute Lung Infection

2018 ◽  
Vol 217 (9) ◽  
pp. 1481-1490 ◽  
Author(s):  
Sivakumar Periasamy ◽  
Jonathan A Harton
Keyword(s):  
Interleukin 1 ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Interleukin 10 ◽  
Dual Function ◽  
Interleukin 17 ◽  
Colony Stimulating Factor ◽  
Immature Myeloid Cells ◽  
Severe Pathology ◽  
Stimulating Factor

Abstract Bacterial pneumonia is a common risk factor for acute lung injury and sepsis-mediated death, but the mechanisms underlying the overt inflammation and accompanying pathology are unclear. Infiltration of immature myeloid cells and necrotizing inflammation mediate severe pathology and death during pulmonary infection with Francisella tularensis. However, eliciting mature myeloid cells provides protection. Yet, the host factors responsible for this pathologic immature myeloid cell response are unknown. Here, we report that while the influx of both mature and immature myeloid cells is strictly MyD88 dependent, the interleukin 1 (IL-1) receptor mediates an important dual function via its ligands IL-1α and IL-1β. Although IL-1β favors the appearance of bacteria-clearing mature myeloid cells, IL-1α contributes to lung infiltration by ineffective and pathologic immature myeloid cells. Finally, IL-1α and IL-1β are not the sole factors involved, but myeloid cell responses during acute pneumonia were largely unaffected by lung levels of interleukin 10, interleukin 17, CXCL1, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor.

scholarly journals The long non-coding RNA LUCAT1 is a negative feedback regulator of interferon responses in humans

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shiuli Agarwal ◽  
Tim Vierbuchen ◽  
Sreya Ghosh ◽  
Jennie Chan ◽  
Zhaozhao Jiang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Myeloid Cells ◽  
Type I ◽  
Targeted Deletion ◽  
Interferon Stimulated Genes ◽  
Non Coding Rna ◽  
Interferon Responses ◽  
Long Non Coding Rna ◽  
Feedback Regulator

AbstractLong non-coding RNAs are important regulators of biological processes including immune responses. The immunoregulatory functions of lncRNAs have been revealed primarily in murine models with limited understanding of lncRNAs in human immune responses. Here, we identify lncRNA LUCAT1 which is upregulated in human myeloid cells stimulated with lipopolysaccharide and other innate immune stimuli. Targeted deletion of LUCAT1 in myeloid cells increases expression of type I interferon stimulated genes in response to LPS. By contrast, increased LUCAT1 expression results in a reduction of the inducible ISG response. In activated cells, LUCAT1 is enriched in the nucleus where it associates with chromatin. Further, LUCAT1 limits transcription of interferon stimulated genes by interacting with STAT1 in the nucleus. Together, our study highlights the role of the lncRNA LUCAT1 as a post-induction feedback regulator which functions to restrain the immune response in human cells.

Myeloid-Derived Suppressor Cells Increase in Chronic Myeloid Leukemia and Exert Immune Suppressive Activity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2779-2779
Author(s):  
Cesarina Giallongo ◽  
Nunziatina Parrinello ◽  
Daniele Tibullo ◽  
Piera La Cava ◽  
Alessandra Cupri ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Enzymatic Activity ◽  
Myeloid Leukemia ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Derived Suppressor Cells ◽  
Arginase 1

Abstract Abstract 2779 Background: Tumor cells are able to develop immune evasion mechanisms which induce a state of immune tolerance and inactivate tumor-specific T cells. In this context, in some solid tumors it has been demonstrated that a subpopulation of myeloid cells, defined as “myeloid-derived suppressor cells” (MDSCs), plays an important role in inducing T cell tolerance by production of arginase that depletes microenvironment of arginine, an essential aminoacid for T cell function. Since chronic myeloid leukemia (CML) patients have high levels of immature myeloid cells it is of interest to investigate if these cells have MDSCs phenotype and activity. Aim: The aim of this study was to analyze MDSCs and investigate their involvement in T-cell anergy of CML patients. Methods: MDSCs were analyzed in peripheral blood (PB) of 13 CML patients (at diagnosis and during therapy) and healthy donors (HD; n=20) by cytofluorimetric analysis (CD14+DR- for monocytic MDSCs and CD11b+CD33+CD14-DR- for granulocytic MDSCs). Arginase 1 expression was assessed in PB of HD and CML patient using real time PCR. Purification of granulocytes, monocytes and lymphocytes from PB was performed by a positive magnetic separation kit (EasySep, STEMCELL Technologies). Arginase activity was measured in granulocyte lysates using a colorimetric test after enzymatic activation and arginine hydrolysis. To evaluate the activation of CD3+ T lymphocytes after incubation with phytoemagglutinin, we analyzed at 24, 48, 72 h the following markers: CD69+, CD71+, DR+. Microvesicles were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. Results: CML patients showed high levels of monocytic and granulocytic MDSCs at diagnosis in comparison to HD (63±8 and 83±12,2% respectively in CML vs 4,9±2,1 and 55,8±5,3% respectively in HD; p<0.001) while after 3–6 months of tyrosine kinase inhibitors (TKIs) therapy MDSC levels returned to normal values. Either in PB and in the purified granulocytes subpopulation, arginase1 expression showed a 30 fold increase in CML at diagnosis (CML vs HD: p<0.01) and decreased after therapy. We also evaluated arginase enzymatic activity in granulocytes and we found it increased in CML patients (n=4) compared to HD (n=5) (p<0.05). CML as well as HD T lymphocytes showed a normal activation in vitro which was significantly lost when they was incubated with CML serum (n=4). In addition, an increase of monocytic MDSCs in vitro was observed after incubation of HD monocytes with CML serum (39±6%; p<0.01) or microvescicles (9,2±1,2%; p<0.05) compared to control serum. Conclusions: Granulocytic and monocytic MDSCs are increased in CML patients at diagnosis and decrease during TKIs treatment. Their levels also correlates with Arginase 1 expression and enzymatic activity in granulocytes. CML serum as well as CML microvesicles increase the percentage of HD monocytic MDSCs. Moreover, CML serum leads to anergy of T lymphocytes, probably by Arginase 1 secretion. Disclosures: Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP).

scholarly journals Elucidating the Role of Host Long Non-Coding RNA during Viral Infection: Challenges and Paths Forward

Vaccines ◽  
2017 ◽  
Vol 5 (4) ◽  
pp. 37 ◽  
Author(s):  
David J. Lemler ◽  
Hayden N. Brochu ◽  
Fang Yang ◽  
Erin A. Harrell ◽  
Xinxia Peng
Keyword(s):  
Viral Infection ◽  
Non Coding Rna ◽  
Long Non Coding Rna
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