scholarly journals Hypothermia modulates myeloid cell polarization in neonatal hypoxic–ischemic brain injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Marina Seitz ◽  
Christian Köster ◽  
Mark Dzietko ◽  
Hemmen Sabir ◽  
Meray Serdar ◽  
...  
Keyword(s):  
Brain Injury ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Neuronal Loss ◽  
Myeloid Cell ◽  
Microglia Activation ◽  
Body Core Temperature ◽  
Marker Genes ◽  
Newborn Mice ◽  
The Impact

Abstract Background Neonatal encephalopathy due to hypoxia–ischemia (HI) is a leading cause of death and disability in term newborns. Therapeutic hypothermia (HT) is the only recommended therapy. However, 30% still suffer from neurological deficits. Inflammation is a major hallmark of HI pathophysiology with myeloid cells being key players, participating either in progression or in resolution of injury-induced inflammation. In the present study, we investigated the impact of HT on the temporal and spatial dynamics of microglia/macrophage polarization after neonatal HI in newborn mice. Methods Nine-day-old C57BL/6 mice were exposed to HI through occlusion of the right common carotid artery followed by 1 h hypoxia. Immediately after HI, animals were cooled for 4 h or kept at physiological body core temperature. Analyses were performed at 1, 3 and 7 days post HI. Brain injury, neuronal cell loss, apoptosis and microglia activation were assessed by immunohistochemistry. A broad set of typical genes associated with classical (M1) and alternative (M2) myeloid cell activation was analyzed by real time PCR in ex vivo isolated CD11b+ microglia/macrophages. Purity and composition of isolated cells was determined by flow cytometry. Results Immediate HT significantly reduced HI-induced brain injury and neuronal loss 7 days post HI, whereas only mild non-significant protection from HI-induced apoptosis and neuronal loss were observed 1 and 3 days after HI. Microglia activation, i.e., Iba-1 immunoreactivity peaked 3 days after HI and was not modulated by HT. However, ex vivo isolated CD11b+ cells revealed a strong upregulation of the majority of M1 but also M2 marker genes at day 1, which was significantly reduced by HT and rapidly declined at day 3. HI induced a significant increase in the frequency of peripheral macrophages in sorted CD11b+ cells at day 1, which deteriorated until day 7 and was significantly decreased by HT. Conclusion Our data demonstrate that HT-induced neuroprotection is preceded by acute suppression of HI-induced upregulation of inflammatory genes in myeloid cells and decreased infiltration of peripheral macrophages, both representing potential important effector mechanisms of HT.

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 PARP-1 Inhibition Attenuates Neuronal Loss, Microglia Activation and Neurological Deficits after Traumatic Brain Injury

2014 ◽  
Vol 31 (8) ◽  
pp. 758-772 ◽  
Author(s):  
Bogdan A. Stoica ◽  
David J. Loane ◽  
Zaorui Zhao ◽  
Shruti V. Kabadi ◽  
Marie Hanscom ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Loss ◽  
Microglia Activation ◽  
Neurological Deficits ◽  
Parp 1

scholarly journals NOX2-Derived Reactive Oxygen Species in Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Hanna Grauers Wiktorin ◽  
Ebru Aydin ◽  
Kristoffer Hellstrand ◽  
Anna Martner
Keyword(s):  
Reactive Oxygen Species ◽  
Antitumor Immunity ◽  
Somatic Mutations ◽  
Myeloid Cells ◽  
Reactive Oxygen ◽  
Myeloid Cell ◽  
Redox Balance ◽  
Cytotoxic Lymphocytes ◽  
Oxygen Species ◽  
The Impact

The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer.

scholarly journals Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy

Blood ◽  
2010 ◽  
Vol 115 (7) ◽  
pp. 1461-1471 ◽  
Author(s):  
Saul J. Priceman ◽  
James L. Sung ◽  
Zory Shaposhnik ◽  
Jeremy B. Burton ◽  
Antoni X. Torres-Collado ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Angiogenesis ◽  
Antiangiogenic Therapy ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Compensatory Mechanism ◽  
Tumor Resistance ◽  
And Function ◽  
The Impact

Abstract Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b+F4/80+ tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b+Gr-1loLy6Chi mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti–VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages

2020 ◽  
Vol 32 (12) ◽  
pp. 785-798
Author(s):  
Ryota Sato ◽  
Tatjana Reuter ◽  
Ryosuke Hiranuma ◽  
Takuma Shibata ◽  
Ryutaro Fukui ◽  
...  
Keyword(s):  
Protein Expression ◽  
Kupffer Cells ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Toll Like Receptors ◽  
Mhc Ii ◽  
Monocytes And Macrophages ◽  
Differentiation Status ◽  
The Impact ◽  
Patrolling Monocytes

Abstract Toll-like receptors (TLRs) impact myeloid cell responsiveness to environmental cues such as pathogen components and metabolites. Although TLR protein expression in monocytes and tissue macrophages is thought to be optimized for microenvironments in each tissue, a comprehensive study has not been reported. We here examined protein expression of endogenous TLRs in tissue-resident myeloid cells. Neutrophils in peripheral blood, spleen, liver and lung expressed TLR2, TLR4 and TLR5 in all tissues. Ly6C+ MHC II‒ classical monocytes mature into Ly6C‒ MHC II+ monocyte-derived dendritic cells (moDCs) or Ly6C‒ MHC II‒ patrolling monocytes. These subsets were found in all the tissues studied. TLR2 and TLR4 were displayed on all of these subsets, regardless of location. In contrast, expression of endosomal TLRs did vary with tissues and subsets. moDCs expressed TLR9, but much less TLR7. In contrast, TLR7, not TLR3 or TLR9, was highly expressed in classical and patrolling monocytes. Tissue macrophages such as red pulp macrophages in the spleen, Kupffer cells in the liver, microglia in the brain, alveolar macrophages in the lung and adipose tissue macrophages all expressed TLR2, TLR4 and TLR3. TLR7 was also expressed in these tissue macrophages except Kupffer cells in the liver. TLR9 expression in tissue macrophages was much lower or hard to detect. These results suggest that expression of endosomal TLRs in myeloid cells is influenced by their differentiation status and tissue-specific microenvironments.

scholarly journals Ratios between circulating myeloid cells and lymphocytes are associated with mortality in severe COVID-19 patients

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 351-360
Author(s):  
Hui Ma ◽  
Xiong Chang Lim ◽  
Qihong Yu ◽  
Yi Li ◽  
Yuechuan Li ◽  
...  
Keyword(s):  
Myeloid Cells ◽  
Myeloid Cell ◽  
Laboratory Findings ◽  
Lymphocyte Ratio ◽  
Host Immune Responses ◽  
Cell Counts ◽  
Coagulation Status ◽  
Highly Correlated ◽  
The Impact ◽  
D Dimer

Abstract Recent studies indicate that host immune responses are dysregulated with either myeloid cell compartment or lymphocyte composition being disturbed in COVID-19. This study aimed to assess the impact of SARS-CoV-2 viral infection on the composition of circulating immune cells in severe COVID-19 patients. In this retrospective single-center cohort, 71 out of 87 COVID-19 patients admitted to the intense care unit for oxygen treatment were included in this study. Demographics, clinical features, comorbidities, and laboratory findings were collected on admission. Out of the 71 patients, 5 died from COVID-19. Compared with survived patients, deceased patients showed higher blood cell counts of neutrophils and monocytes but lower cell counts of lymphocytes. Intriguingly, the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and basophil-to-lymphocyte ratio (BLR) were markedly higher in deceased patients compared to survived patients. Furthermore, the lymphocyte counts were negatively correlated with D-dimer levels, while the ratios between myeloid cells and lymphocyte (NLR, MLR, and BLR) were positively correlated with D-dimer levels. Our findings revealed that the ratios between myeloid cells and lymphocytes were highly correlated with coagulation status and patient mortality in severe COVID-19.

scholarly journals A Proteomic Atlas of Lineage and Cancer-Polarized Expression Modules in Myeloid Cells Modeling Immunosuppressive Tumor-Infiltrating Subsets

2021 ◽  
Vol 11 (6) ◽  
pp. 542
Author(s):  
Ester Blanco ◽  
Maria Ibañez-Vea ◽  
Carlos Hernandez ◽  
Lylia Drici ◽  
Xabier Martínez de Morentin ◽  
...  
Keyword(s):  
Quantitative Proteomics ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Cell Types ◽  
Biological Processes ◽  
New Treatments ◽  
High Throughput Experiments ◽  
Model Tumor

Monocytic and granulocytic myeloid-derived suppressor cells together with tumor-infiltrating macrophages constitute the main tumor-infiltrating immunosuppressive myeloid populations. Due to the phenotypic resemblance to conventional myeloid cells, their identification and purification from within the tumors is technically difficult and makes their study a challenge. We differentiated myeloid cells modeling the three main tumor-infiltrating types together with uncommitted macrophages, using ex vivo differentiation methods resembling the tumor microenvironment. The phenotype and proteome of these cells was compared to identify linage-dependent relationships and cancer-specific interactome expression modules. The relationships between monocytic MDSCs and TAMs, monocytic MDSCs and granulocytic MDSCs, and hierarchical relationships of expression networks and transcription factors due to lineage and cancer polarization were mapped. Highly purified immunosuppressive myeloid cell populations that model tumor-infiltrating counterparts were systematically analyzed by quantitative proteomics. Full functional interactome maps have been generated to characterize at high resolution the relationships between the three main myeloid tumor-infiltrating cell types. Our data highlights the biological processes related to each cell type, and uncover novel shared and differential molecular targets. Moreover, the high numbers and fidelity of ex vivo-generated subsets to their natural tumor-shaped counterparts enable their use for validation of new treatments in high-throughput experiments.

scholarly journals The Metabolic Control of Myeloid Cells in the Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2960
Author(s):  
Eloise Ramel ◽  
Sebastian Lillo ◽  
Boutaina Daher ◽  
Marina Fioleau ◽  
Thomas Daubon ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Phenotypic Diversity ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Mass Cytometry ◽  
Cell Functions ◽  
Metabolic Checkpoints ◽  
The Impact

Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell’s metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.

scholarly journals In situ transcriptome characteristics are lost following culture adaptation of adult cardiac stem cells

2018 ◽  
Author(s):  
Taeyong Kim ◽  
Oscar H. Echeagaray ◽  
Bingyan J Wang ◽  
Alexandria Casillas ◽  
Kathleen M. Broughton ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Population Heterogeneity ◽  
Cell Populations ◽  
Marker Genes ◽  
Interventional Treatment ◽  
Phenotypic Characteristics ◽  
Isolated Cells ◽  
The Impact

AbstractRegenerative therapeutic approaches for myocardial diseases often involve adoptive transfer of stem cells expanded ex vivo. Prior studies indicate that cell culture conditions affect functional and phenotypic characteristics, but relationship(s) of cultured cells derived from freshly isolated populations and the heterogeneity of the cultured population remain poorly defined. Functional and phenotypic characteristics of adoptively donated cells will determine outcomes of interventional treatment for disease, necessitating characterization of the impact that ex vivo expansion has upon isolated stem cell populations. Single-cell RNA-Seq profiling (scRNA-Seq) was performed to determine consequences of culture expansion upon adult cardiac progenitor cells (CPCs) as well as relationships with other cell populations. Bioinformatic analyses reveal loss of identity marker genes in cultured CPCs while simultaneously acquiring thousands of additional genes. Cultured CPCs exhibited decreased transcriptome variability within their population relative to their freshly isolated cells. Findings were validated by comparative analyses using scRNA-Seq datasets of various cell types generated by multiple scRNA-Seq technology. Increased transcriptome diversity and decreased population heterogeneity in the cultured cell population relative to freshly isolated cells may help account for reported outcomes associated with experimental and clinical use of CPCs for treatment of myocardial injury.

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