scholarly journals HIV-1 Nef induces Hck/Lyn-dependent expansion of MDSC associated with elevated IL-17/G-CSF

2021 ◽  
Author(s):  
Elena Priceputu ◽  
Marc Cool ◽  
Nathalie Bouchard ◽  
Julio Roberto Caceres-Cortes ◽  
Clifford A. Lowell ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cell Expansion ◽  
Bystander Effect ◽  
Fetal Liver ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Erythroid Progenitors ◽  
Inflammatory Monocytes ◽  
Siv Infection ◽  
Hiv 1

HIV or SIV infection causes myelodysplasia, anemia and accumulation of inflammatory monocytes (CD14 + CD16 + ), through largely unknown cellular and molecular pathways. The mouse cells thought to be equivalent to human CD14 + CD16 + cells are CD11b + Gr1 + myeloid-derived suppressive cells (MDSC). We used HIV transgenic (Tg) mouse models to study MDSC, namely CD4C/Nef Tg mice expressing nef in dendritic cells (DC), pDC, CD4 + T and other mature and immature myeloid cells and CD11c/Nef Tg mice with a more restricted expression, mainly in DC and pDC. Both Tg strains showed expansion of granulocytic and CD11b + Gr1 low/int cells with MDSC characteristics. Fetal liver cell transplantation revealed that this expansion was stroma-independent and abrogated in mixed Tg/non-Tg 50% chimera. Tg bone marrow (BM) erythroid progenitors were decreased and myeloid precursors increased, suggesting an aberrant differentiation likely driving CD11b + Gr1 + cell expansion, apparently cell-autonomously in CD4C/Nef Tg mice and likely through a bystander effect in CD11c/Nef Tg mice. Hck was activated in Tg spleen, and Nef-mediated CD11b + Gr1 + cell expansion was abrogated in Hck/Lyn-deficient Nef Tg mice, indicating a requirement of Hck/Lyn for this Nef function. IL-17 and G-CSF were elevated in Nef Tg mice. Increased G-CSF levels were normalized in Tg mice treated with anti-IL-17 antibodies. Therefore, Nef expression in myeloid precursors causes severe BM failure, apparently cell-autonomously. More cell-restricted expression of Nef in DC and pDC, appears sufficient to induce BM differentiation impairment, granulopoiesis and expansion of MDSC, at the expense of erythroid maturation, through IL-17 → G-CSF, as one likely bystander contributor. IMPORTANCE HIV-1 and SIV infection often lead to myelodysplasia, anemia and accumulation of inflammatory monocytes (CD14+ CD16+), the latter likely involved in neuroAIDS. We found that some transgenic (Tg) mouse models of AIDS also develop accumulation of mature and immature cells of the granulocytic lineage, decreased erythroid precursors and expansion of MDSC (equivalent to human CD14+ CD16+ cells). We identified Nef as being responsible for these phenotypes and its expression in mouse DC appears sufficient for their development, through a bystander mechanism. Nef expression in myeloid progenitors may also favor myeloid cell expansion, likely in a cell-autonomous way. Hck/Lyn is required for the Nef-mediated accumulation of myeloid cells. Finally, we identified G-CSF under the control of IL-17 as one bystander mediator of MDSC expansion. Our findings provide a framework to determine whether the Nef>Hck/Lyn>IL-17>G-CSF pathway is involved in human AIDS and whether it represents a valid therapeutic target.

scholarly journals A novel transcript encoding an N-terminally truncated AML1/PEBP2 alphaB protein interferes with transactivation and blocks granulocytic differentiation of 32Dcl3 myeloid cells.

1997 ◽  
Vol 17 (7) ◽  
pp. 4133-4145 ◽  
Author(s):  
Y W Zhang ◽  
S C Bae ◽  
G Huang ◽  
Y X Fu ◽  
J Lu ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Protein Product ◽  
Terminal Region ◽  
Human Leukemia ◽  
Granulocytic Differentiation ◽  
Runt Domain ◽  
Rnase Protection ◽  
Novel Transcript

The gene AML1/PEBP2 alphaB encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal liver hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms have been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities. We have identified a new isoform of the AML1 transcript, termed AML1 deltaN, in which exon 1 is directly connected to exon 4 by alternative splicing. The AML1 deltaN transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protection and reverse transcriptase PCR analyses. The protein product of AML1 deltaN lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the beta subunit. However, AML1 deltaN was found to interfere with the transactivation activity of PEBP2, and the molecular region responsible for this activity was identified. Stable expression of AML1 deltaN in 32Dcl3 myeloid cells blocked granulocytic differentiation in response to granulocyte colony-stimulating factor. These results suggest that AML1 deltaN acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AML1.

scholarly journals Myeloid Cells during Viral Infections and Inflammation

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 168 ◽  
Author(s):  
Ashley A. Stegelmeier ◽  
Jacob P. van Vloten ◽  
Robert C. Mould ◽  
Elaine M. Klafuric ◽  
Jessica A. Minott ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Biology ◽  
Viral Infections ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Host Responses ◽  
Signaling Cascade ◽  
Diverse Range ◽  
Inflammatory Monocytes ◽  
Molecular Patterns

Myeloid cells represent a diverse range of innate leukocytes that are crucial for mounting successful immune responses against viruses. These cells are responsible for detecting pathogen-associated molecular patterns, thereby initiating a signaling cascade that results in the production of cytokines such as interferons to mitigate infections. The aim of this review is to outline recent advances in our knowledge of the roles that neutrophils and inflammatory monocytes play in initiating and coordinating host responses against viral infections. A focus is placed on myeloid cell development, trafficking and antiviral mechanisms. Although known for promoting inflammation, there is a growing body of literature which demonstrates that myeloid cells can also play critical regulatory or immunosuppressive roles, especially following the elimination of viruses. Additionally, the ability of myeloid cells to control other innate and adaptive leukocytes during viral infections situates these cells as key, yet under-appreciated mediators of pathogenic inflammation that can sometimes trigger cytokine storms. The information presented here should assist researchers in integrating myeloid cell biology into the design of novel and more effective virus-targeted therapies.

scholarly journals Vpx enhances innate immune responses independently of SAMHD1 during HIV-1 infection

Retrovirology ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Oya Cingöz ◽  
Nicolas D. Arnow ◽  
Mireia Puig Torrents ◽  
Norbert Bannert
Keyword(s):  
Immune Responses ◽  
Cell Lines ◽  
Myeloid Cells ◽  
Adaptor Protein ◽  
Myeloid Cell ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Accessory Gene ◽  
Monocytic Cell ◽  
Hiv 1

Abstract Background The genomes of HIV-2 and some SIV strains contain the accessory gene vpx, which carries out several functions during infection, including the downregulation of SAMHD1. Vpx is also commonly used in experiments to increase HIV-1 infection efficiency in myeloid cells, particularly in studies that investigate the activation of antiviral pathways. However, the potential effects of Vpx on cellular innate immune signaling is not completely understood. We investigated whether and how Vpx affects ISG responses in monocytic cell lines and MDMs during HIV-1 infection. Results HIV-1 infection at excessively high virus doses can induce ISG activation, although at the expense of high levels of cell death. At equal infection levels, the ISG response is potentiated by the presence of Vpx and requires the initiation of reverse transcription. The interaction of Vpx with the DCAF1 adaptor protein is important for the enhanced response, implicating Vpx-mediated degradation of a host factor. Cells lacking SAMHD1 show similarly augmented responses, suggesting an effect that is independent of SAMHD1 degradation. Overcoming SAMHD1 restriction in MDMs to reach equal infection levels with viruses containing and lacking Vpx reveals a novel function of Vpx in elevating innate immune responses. Conclusions Vpx likely has as yet undefined roles in infected cells. Our results demonstrate that Vpx enhances ISG responses in myeloid cell lines and primary cells independently of its ability to degrade SAMHD1. These findings have implications for innate immunity studies in myeloid cells that use Vpx delivery with HIV-1 infection.

scholarly journals 2013 Russell Ross Memorial Lecture in Vascular Biology

2014 ◽  
Vol 34 (4) ◽  
pp. 705-714 ◽  
Author(s):  
Karin E. Bornfeldt
Keyword(s):  
Diabetes Mellitus ◽  
Mouse Models ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Genetically Engineered ◽  
Memorial Lecture ◽  
Protective Effects ◽  
Atherosclerotic Lesions ◽  
Lesion Regression ◽  
Cell Expression

Adults with diabetes mellitus are much more likely to have cardiovascular disease than those without diabetes mellitus. Genetically engineered mouse models have started to provide important insight into the mechanisms whereby diabetes mellitus promotes atherosclerosis. Such models have demonstrated that diabetes mellitus promotes formation of atherosclerotic lesions, progression of lesions into advanced hemorrhaged lesions, and that it prevents lesion regression. The proatherosclerotic effects of diabetes mellitus are driven in part by the altered function of myeloid cells. The protein S100A9 and the receptor for advanced glycation end-products are important modulators of the effect of diabetes mellitus on myelopoiesis, which might promote monocyte accumulation in lesions. Furthermore, myeloid cell expression of the enzyme acyl-CoA synthetase 1 (ACSL1), which converts long-chain fatty acids into their acyl-CoA derivatives, has emerged as causal to diabetes mellitus–induced lesion initiation. The protective effects of myeloid ACSL1-deficiency in diabetic mice, but not in nondiabetic mice, indicate that myeloid cells are activated by diabetes mellitus through mechanisms that play minor roles in the absence of diabetes mellitus. The roles of reactive oxygen species and insulin resistance in diabetes mellitus–accelerated atherosclerosis are also discussed, primarily in relation to endothelial cells. Translational studies addressing whether the mechanisms identified in mouse models are equally important in humans with diabetes mellitus will be paramount.

Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2138-2145 ◽  
Author(s):  
Cecilia Melani ◽  
Claudia Chiodoni ◽  
Guido Forni ◽  
Mario P. Colombo
Keyword(s):  
Cell Expansion ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Immune Reactivity ◽  
Mammary Carcinomas ◽  
Gm Csf ◽  
Tumor Load ◽  
Tumor Virus ◽  
Immature Myeloid Cells ◽  
Macrophage Colony

Abstract Transgenic female mice expressing the transforming rat oncogene c-erbB-2 (HER-2/neu) under the mouse mammary tumor virus (MMTV) promoter (BALB-neuT) spontaneously develop mammary carcinomas with a progression resembling that of human breast cancer. In these mice, activating antitumor immunotherapy fails to induce T cell–mediated cytotoxicity, suggesting a suppression of the immune response. We found a direct correlation between tumor multiplicity and an increased proportion of Gr-1+ (Ly6G)/Mac-1+(CD11b)/ER-MP12+(CD31) immature myeloid cells in the peripheral blood (PB) and spleen, suggesting that tumor load profoundly affects overall BALB-neuT hematopoiesis. In fact, myeloid colony formation was increased in bone marrow (BM) and spleen. The immature myeloid cells displayed suppressive activity on host T lymphocytes, which progressively failed to respond to alloantigens and CD3 triggering, while maintaining the ability to proliferate in response to nonspecific mitogens. Transplantation of normal BM into BALB-neuT mice readily resulted in hypertrophic hematopoiesis with myeloid cell expansion. This persistent influence of the tumor was mediated through the release of vascular endothelial growth factor (VEGF) but not granulocyte-macrophage colony-stimulating factor (GM-CSF), and was down-modulated when tumor load was reduced but not when BM was transplanted. Together, the data obtained in the BALB-neuT model of naturally occurring carcinogenesis show that tumor-associated immune suppression is secondary to a more general alteration of host hematopoiesis, conditioned by tumor-secreted soluble factors.

ADAM10 Partially Protects Mice against Influenza Pneumonia by Suppressing Specific Myeloid Cell Population

2021 ◽  
Author(s):  
Satoshi Okamori ◽  
Makoto Ishii ◽  
Takanori Asakura ◽  
Shoji Suzuki ◽  
Ho Namkoong ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Myeloid Cells ◽  
Influenza Virus Infection ◽  
Virus Titer ◽  
Myeloid Cell ◽  
Immune Defense ◽  
Gm Csf ◽  
Inflammatory Monocytes ◽  
Arginase 1

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contribute to various immune responses; however, the role of ADAM10 in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. Adam10flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines such as TNF-α, IL-1b, and CCL2 were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocytes/macrophages-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, while an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

scholarly journals Alzheimer’s patient brain myeloid cells exhibit enhanced aging and unique transcriptional activation

2019 ◽  
Author(s):  
Karpagam Srinivasan ◽  
Brad A. Friedman ◽  
Ainhoa Etxeberria ◽  
Melanie A. Huntley ◽  
Marcel P. van der Brug ◽  
...  
Keyword(s):  
Mouse Models ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Expression Profiles ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Fresh Tissue ◽  
A Genome

AbstractGene expression changes in brain microglia from mouse models of Alzheimer’s disease (AD) are highly characterized and reflect specific myeloid cell activation states that could modulate AD risk or progression. While some groups have produced valuable expression profiles for human brain cells1–4, the cellular clarity with which we now view transcriptional responses in mouse AD models has not yet been realized for human AD tissues due to limited availability of fresh tissue samples and technological hurdles of recovering transcriptomic data with cell-type resolution from frozen samples. We developed a novel method for isolating multiple cell types from frozen post-mortem specimens of superior frontal gyrus for RNA-Seq and identified 66 genes differentially expressed between AD and control subjects in the myeloid cell compartment. Myeloid cells sorted from fusiform gyrus of the same subjects showed similar changes, and whole tissue RNA analyses further corroborated our findings. The changes we observed did not resemble the “damage-associated microglia” (DAM) profile described in mouse AD models5, or other known activation states from other disease models. Instead, roughly half of the changes were consistent with an “enhanced human aging” phenotype, whereas the other half, including the AD risk gene APOE, were altered in AD myeloid cells but not differentially expressed with age. We refer to this novel profile in human Alzheimer’s microglia/myeloid cells as the HAM signature. These results, which can be browsed at research-pub.gene.com/BrainMyeloidLandscape/reviewVersion, highlight considerable differences between myeloid activation in mouse models and human disease, and provide a genome-wide picture of brain myeloid activation in human AD.

scholarly journals Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease

2015 ◽  
Vol 212 (11) ◽  
pp. 1803-1809 ◽  
Author(s):  
Nicholas H. Varvel ◽  
Stefan A. Grathwohl ◽  
Karoline Degenhardt ◽  
Claudia Resch ◽  
Andrea Bosch ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Myeloid Cell ◽  
Functional Roles ◽  
Amyloid Load

Immune cells of myeloid lineage are encountered in the Alzheimer’s disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.

scholarly journals Colony-Stimulating Factor 1 Receptor Antagonists Sensitize Human Immunodeficiency Virus Type 1-Infected Macrophages to TRAIL-Mediated Killing

2016 ◽  
Vol 90 (14) ◽  
pp. 6255-6262 ◽  
Author(s):  
Francesc Cunyat ◽  
Jennifer N. Rainho ◽  
Brian West ◽  
Louise Swainson ◽  
Joseph M. McCune ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiviral Therapy ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Virus Reactivation ◽  
Colony Stimulating Factor ◽  
Viral Reservoirs ◽  
Stimulating Factor ◽  
Hiv 1

ABSTRACTStrategies aimed at eliminating persistent viral reservoirs from HIV-1-infected individuals have focused on CD4+T-cell reservoirs. However, very little attention has been given to approaches that could promote elimination of tissue macrophage reservoirs. HIV-1 infection of macrophages induces phosphorylation of colony-stimulating factor 1 receptor (CSF-1R), which confers resistance to apoptotic pathways driven by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), thereby promoting viral persistence. In this study, we assessed whether CSF-1R antagonists (PLX647, PLX3397, and PLX5622) restored apoptotic sensitivity of HIV-1-infected macrophagesin vitro. PLX647, PLX3397, and PLX5622 at clinically relevant concentrations blocked the activation of CSF-1R and reduced the viability of infected macrophages, as well as the extent of viral replication. Our data show that strategies targeting monocyte colony-stimulating factor (MCSF) signaling could be used to promote elimination of HIV-1-infected myeloid cells and to contribute to the elimination of persistent viral reservoirs.IMPORTANCEAs the HIV/AIDS research field explores approaches to eliminate HIV-1 in individuals on suppressive antiviral therapy, those approaches will need to eliminate both CD4+T-cell and myeloid cell reservoirs. Most of the attention has focused on CD4+T-cell reservoirs, and scant attention has been paid to myeloid cell reservoirs. The distinct nature of the infection in myeloid cells versus CD4+T cells will likely dictate different approaches in order to achieve their elimination. For CD4+T cells, most strategies focus on promoting virus reactivation to promote immune-mediated clearance and/or elimination by viral cytopathicity. Macrophages resist viral cytopathic effects and CD8+T-cell killing. Therefore, we have explored clearance strategies that render macrophages sensitive to viral cytopathicity. This research helps inform the design of strategies to promote clearance of the macrophage reservoir in infected individuals on suppressive antiviral therapy.

scholarly journals Targeting CSF-1 ameliorates experimental autoimmune encephalomyelitis by depleting inflammatory monocytes and microglia in the central nervous system without affecting quiescent microglia

2020 ◽  
Author(s):  
Daniel Hwang ◽  
Larissa Lumi Watanabe Ishikawa ◽  
Alexandra Boehm ◽  
Ziver Sahin ◽  
Giacomo Casella ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Monocytes ◽  
The Central Nervous System ◽  
Spleen And Lymph Nodes ◽  
Experimental Autoimmune

ABSTRACTMultiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by extensive infiltration of myeloid cells into the central nervous system (CNS). Although myeloid cells are essential to MS/EAE pathology, none of the current MS therapies specifically target them. A promising strategy for bridging this gap may be targeting the biological activity of CSF-1R, a receptor tyrosine kinase important for survival and functioning of certain myeloid cells, such as monocytes and macrophages. It has been shown that CSF-1R inhibitors suppress EAE, but it is not known whether targeting CSF-1R ligands, CSF-1 and IL-34, could be a viable therapeutic strategy. We found that neutralization of CSF-1 with Ab attenuates ongoing EAE, similar to CSF-1R inhibitor BLZ945, whereas neutralization of IL-34 had no effect. Both anti-CSF-1- and BLZ945-treated mice with EAE had greatly diminished numbers of monocyte-derived dendritic cells and microglia in the CNS. However, anti-CSF-1 antibody selectively depleted inflammatory microglia, whereas BLZ945 depleted virtually all microglia, including quiescent microglia. We also found depletion of myeloid cells in the spleen and lymph nodes of anti-CSF-1- and BLZ945-treated mice, but only a modest decrease in encephalitogenic T cell responses, suggesting that the depletion of CNS myeloid cells is more relevant to EAE suppression. Decreased myeloid cell populations in treated mice resulted in reduced production of IL-1β, a key inflammatory mediator in EAE. The treatments also reduced the frequencies of CCL2- and CCR2-expressing cells in the CNS, suggesting that CSF-1/CSF-1R inhibition may hinder recruitment of immune cells to the CNS. Our findings suggest that targeting CSF-1 may be effective in ameliorating myeloid cell-mediated MS pathology, while preserving homeostatic functions of microglia and decreasing risks that might arise from their ablation with small molecule inhibitors of CSF-1R.

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