Targeting Piezo1 unleashes innate immunity against cancer and infectious disease

2020 ◽  
Vol 5 (50) ◽  
pp. eabb5168 ◽  
Author(s):  
Berk Aykut ◽  
Ruonan Chen ◽  
Jacqueline I. Kim ◽  
Dongling Wu ◽  
Sorin A. A. Shadaloey ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Immune Regulation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Retinoblastoma Gene ◽  
Histone Deacetylase 2 ◽  
Physiological Processes ◽  
Mechanosensitive Ion Channel ◽  
Physical Forces ◽  
Global Inhibition

Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor immunity, is not well studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We found signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 with a peptide inhibitor was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in polymicrobial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing the retinoblastoma gene Rb1. We further show that Piezo1-mediated silencing of Rb1 is regulated via up-regulation of histone deacetylase 2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immunosuppressive myelopoiesis in cancer and infectious disease.

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.

Targeting Trained Innate Immunity With Nanobiologics to Treat Cardiovascular Disease

2021 ◽  
Author(s):  
Abraham J.P. Teunissen ◽  
Mandy M.T. van Leent ◽  
Geoffrey Prevot ◽  
Eliane E.S. Brechbuhl ◽  
Carlos Pérez-Medina ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Apolipoprotein A1 ◽  
New Paradigm ◽  
Trained Immunity ◽  
Atherosclerosis Progression ◽  
Cardiovascular Patients ◽  
Cellular Pathways

The innate immune system plays a key role in atherosclerosis progression and the pathogenesis of cardiovascular disease. Trained immunity, an epigenetically regulated hyperresponsive state of myeloid cells, is a driving force underlying chronic inflammation in atherosclerosis. Therapeutically targeting innate trained immunity therefore may mature into a compelling new paradigm for the effective treatment of cardiovascular patients, which would require effective engagement of myeloid cells. For over a decade, we have worked on apolipoprotein A1-based nanomaterials, referred to as nanobiologics, which we have utilized for myeloid cell-directed immunotherapy. Here, we review the application of our nanobiologic immunotherapies in treating vascular disease. The design of nanobiologic therapeutics, as well as their use in targeting myeloid cells and cellular pathways related to trained immunity, is discussed. Furthermore, we show that nanobiologic biocompatibility and in vivo behavior are conserved across species, from mice to larger animals, including rabbits, pigs, and nonhuman primates. Last, we deliberate on the hurdles that currently prevent widespread translation of trained immunity targeting cardiovascular nanotherapies.

scholarly journals Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke

2018 ◽  
Vol 39 (10) ◽  
pp. 1906-1918 ◽  
Author(s):  
Kota Kurisu ◽  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Jian Shi ◽  
Atsushi Kanoke ◽  
...  
Keyword(s):  
Cell Activation ◽  
Infarct Volume ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cerebrovascular Diseases ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Neurological Outcomes ◽  
Intact Brain ◽  
The Brain

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.

scholarly journals Endothelial cell-derived CD95 ligand serves as a chemokine in induction of neutrophil slow rolling and adhesion

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Liang Gao ◽  
Gülce Sila Gülcüler ◽  
Lieke Golbach ◽  
Helena Block ◽  
Alexander Zarbock ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Flow Chamber ◽  
Integrin Activation ◽  
Cd95 Ligand ◽  
Slow Rolling

Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells. In myeloid cells, CD95 triggers activation of Syk-Btk/PLCγ2/Rap1 signaling that ultimately leads to integrin activation. Excitingly, CD95-deficient myeloid cells exhibit impaired bacterial clearance in an animal model of sepsis induced by cecal ligation and puncture (CLP). Our data identify the cellular and molecular mechanisms underlying the chemoattractant effect of endothelial cell-derived CD95L in induction of neutrophil recruitment and support the use of therapeutic inhibition of CD95’s activity in inflammatory diseases.

Cell membrane-associated proteoglycans mediate extramedullar myeloid proliferation in granulomatous inflammatory reactions to schistosome eggs

1993 ◽  
Vol 104 (2) ◽  
pp. 477-484
Author(s):  
M. Alvarez-Silva ◽  
L.C. da Silva ◽  
R. Borojevic
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Connective Tissue ◽  
Endogenous Growth ◽  
Cell Lines ◽  
Cell Layer ◽  
Heparan Sulphate ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Gm Csf

In chronic murine schistosomiasis, extramedullar myelopoiesis was observed, with proliferation of myeloid cells in liver parenchyma and in periovular granulomas. We have studied the question of whether cells obtained from granulomatous connective tissue may act as myelopoietic stroma, supporting long-term myeloid proliferation. Primary cell lines (GR) were obtained in vitro from periovular granulomas, induced in mouse livers by Schistosoma mansoni infection. These cells were characterized as myofibroblasts, and represent liver connective tissue cells involved in fibro-granulomatous reactions. They were able to sustain survival and proliferation of the multipotent myeloid cell lines FDC-P1 and DA-1 (dependent on interleukin-3 and/or granulocyte-macrophage colony stimulating factor, GM-CSF) without the addition of exogenous growth factors. This stimulation was dependent upon myeloid cell attachment to the GR cell layer; GR cell-conditioned medium had no activity. Primary murine skin fibroblasts could not sustain myelopoiesis. The endogenous growth-factor was identified as GM-CSF by neutralization assays with monoclonal antibodies. The stimulation of myelopoiesis occurred also when GR cells had been fixed with glutardialdehyde. The observed stimulatory activity was dependent upon heparan sulphate proteoglycans (HSPGs) associated with GR cell membranes. It could be dislodged from the cell layer with heparin or a high salt buffer. Our results indicate a molecular interaction between endogenous growth-factor and HSPGs; this interaction may be responsible for the stabilization and presentation of growth factors in myelopoietic stromas, mediating extramedullar proliferation of myeloid cells in periovular granulomas.

The Myeloid-Kidney Interface in Health and Disease

2021 ◽  
pp. CJN.04120321
Author(s):  
Caitlyn Vlasschaert ◽  
Sarah Moran ◽  
Michael Rauh
Keyword(s):  
Structural Damage ◽  
Functional Decline ◽  
Myeloid Cells ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Surveillance Network ◽  
Targeted Treatments ◽  
Myeloid Leukemias ◽  
Integral Role ◽  
Health And Disease

Kidney homeostasis is highly dependent upon the correct functioning of myeloid cells. These cells form a distributed surveillance network throughout the kidney, where they play an integral role in the response to organ threat. Dysregulation of resident pro-inflammatory and pro-fibrotic macrophages leads to kidney structural damage and scarring following kidney injury. Fibrosis throughout the kidney parenchyma contributes to the progressive functional decline observed in chronic kidney disease (CKD), independent of the etiology. Circulating myeloid cells bearing intrinsic defects also affect the kidney substructures, such as neutrophils activated by autoantibodies that cause glomerulonephritis in ANCA-associated vasculitis. The kidney can also be affected by disorders of myelopoiesis, including myeloid leukemias (AML, CML) and myelodysplastic syndromes (MDS). Clonal hematopoiesis of indeterminate potential (CHIP) is a common, newly recognized pre-malignant clinical entity characterized by clonal expansion of hyper-inflammatory myeloid lineage cells that may have significant kidney sequelae. A number of existing therapies in CKD target myeloid cells and inflammation, including glucocorticoid receptor agonists and mineralocorticoid receptor antagonists. The therapeutic indications for these and other myeloid cell-targeted treatments is poised to expand as our understanding of the myeloid-kidney interface evolves.

IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Tyler Miller ◽  
Chadi El Farran ◽  
Julia Verga ◽  
Charles Couturier ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Low Grade ◽  
Tumor Patients ◽  
The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

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 Metalloprotease activity of CD13/aminopeptidase N on the surface of human myeloid cells

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 462-469 ◽  
Author(s):  
RA Ashmun ◽  
AT Look
Keyword(s):  
Amino Acid ◽  
Cell Surface ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Aminopeptidase N ◽  
Surface Glycoprotein ◽  
Aminopeptidase Activity ◽  
Peptidase Activity ◽  
Cell Surface Glycoprotein ◽  
Metalloprotease Inhibitors

Abstract We previously found that the myeloid cell surface glycoprotein CD13 (gp150) is identical to aminopeptidase N (EC 3.4.11.2), a widely distributed membrane-bound, zinc-dependent metalloprotease with an extracellular enzymatic domain that cleaves N-terminal amino acid residues from oligopeptides (J Clin Invest 83:1299, 1989). As a first step toward defining the function of this molecule on myeloid cells, we assessed cell surface-associated N-terminal peptidase activity by sensitive spectrophotometric measurements of the cleavage of p- nitroanilide amino acid derivatives. Aminopeptidase activity detected on the surface of normal and malignant hematopoietic cells coincided with the level of cell surface CD13 expression as measured by flow cytometry. The enzyme was specifically inhibited by the zinc-binding metalloprotease inhibitors, bestatin, 1,10-phenanthroline, or 2.2′- dipyridyl, but was not affected by several inhibitors of other classes of proteases. Aminopeptidase activity was demonstrated for CD13 molecules specifically immunoprecipitated from the surface of CD13- positive cells and was blocked by the metalloprotease inhibitor 1,10- phenanthroline. Moreover, cell surface aminopeptidase activity was partially inhibited when viable cells were incubated with two of a panel of 11 monoclonal antibodies (MoAbs) known to be specific for extracellular epitopes of human CD13. This inhibition was apparent in the absence of detectable downmodulation of CD13 molecules from the cell surface, suggesting that these MoAbs either physically interfere with substrate binding or alter the zinc-coordinating properties of aminopeptidase N molecules. Aminopeptidase N could play an important role in modulating signals generated by peptides at the surface of myeloid cells, either by removing key N-terminal residues from active peptides or by converting inactive peptides to active forms. The inhibitory antibodies used in this study should prove useful in delineating the physiologic roles of CD13/aminopeptidase N on normal and malignant myeloid cells.

scholarly journals Macromolecular Synthesis Shutoff Resistance by Myeloid Cells Is Critical to IRF7-Dependent Systemic Interferon Alpha/Beta Induction after Alphavirus Infection

2019 ◽  
Vol 93 (24) ◽  
Author(s):  
Nishank Bhalla ◽  
Christina L. Gardner ◽  
Sierra N. Downs ◽  
Matthew Dunn ◽  
Chengqun Sun ◽  
...  
Keyword(s):  
Host Cell ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Cell Types ◽  
Macromolecular Synthesis ◽  
Transcription Inhibition ◽  
Antiviral Responses ◽  
Alphavirus Infection

ABSTRACT Alphavirus infection of fibroblastic cell types in vitro inhibits host cell translation and transcription, leading to suppression of interferon alpha/beta (IFN-α/β) production. However, the effect of infection upon myeloid cells, which are often the first cells encountered by alphaviruses in vivo, is unclear. Previous studies demonstrated an association of systemic IFN-α/β production with myeloid cell infection efficiency. Murine infection with wild-type Venezuelan equine encephalitis virus (VEEV), a highly myeloid-cell-tropic alphavirus, results in secretion of very high systemic levels of IFN-α/β, suggesting that stress responses in responding cells are active. Here, we infected myeloid cell cultures with VEEV to identify the cellular source of IFN-α/β, the timing and extent of translation and/or transcription inhibition in infected cells, and the transcription factors responsible for IFN-α/β induction. In contrast to fibroblast infection, myeloid cell cultures infected with VEEV secreted IFN-α/β that increased until cell death was observed. VEEV inhibited translation in most cells early after infection (<6 h postinfection [p.i.]), while transcription inhibition occurred later (>6 h p.i.). Furthermore, the interferon regulatory factor 7 (IRF7), but not IRF3, transcription factor was critical for IFN-α/β induction in vitro and in sera of mice. We identified a subset of infected Raw 264.7 myeloid cells that resisted VEEV-induced translation inhibition and secreted IFN-α/β despite virus infection. However, in the absence of IFN receptor signaling, the size of this cell population was diminished. These results indicate that IFN-α/β induction in vivo is IRF7 dependent and arises in part from a subset of myeloid cells that are resistant, in an IFN-α/β-dependent manner, to VEEV-induced macromolecular synthesis inhibition. IMPORTANCE Most previous research exploring the interaction of alphaviruses with host cell antiviral responses has been conducted using fibroblast lineage cell lines. Previous studies have led to the discovery of virus-mediated activities that antagonize host cell antiviral defense pathways, such as host cell translation and transcription inhibition and suppression of STAT1 signaling. However, their relevance and impact upon myeloid lineage cell types, which are key responders during the initial stages of alphavirus infection in vivo, have not been well studied. Here, we demonstrate the different abilities of myeloid cells to resist VEEV infection compared to nonmyeloid cell types and begin to elucidate the mechanisms by which host antiviral responses are upregulated in myeloid cells despite the actions of virus-encoded antagonists.

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