scholarly journals G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2868
Author(s):  
Ioannis Karagiannidis ◽  
Eliane de Santana Van Vilet ◽  
Erika Said Abu Egal ◽  
Brandon Phinney ◽  
Damian Jacenik ◽  
...  
Keyword(s):  
Tumor Progression ◽  
No Production ◽  
Macrophage Phenotype ◽  
Pancreas Tumor ◽  
Inflammatory Phenotype ◽  
The Difference ◽  
And Function ◽  
Stimulating Factor

Tumor-associated macrophages (TAMs) in the gastrointestinal tumor microenvironment (TME) are known to polarize into populations exhibiting pro- or anti-tumoral activity in response to stimuli such as growth factors and cytokines. Our previous work has recognized granulocyte colony-stimulating factor (G-CSF) as a cytokine capable of influencing immune cells of the TME exhibiting pro-tumoral activity. Here, we aimed to focus on how G-CSF regulates TAM phenotype and function and the effects on gastrointestinal (GI) tumor progression. Thus, wildtype (WT) and G-CSFR−/− macrophages were examined for cytokine production, gene expression, and transcription factor activity. Adoptive transfer of WT or G-CSFR−/− macrophages into tumor-bearing mice was performed to study their influence in the progression of colon (MC38) and pancreatic (PK5L1940) tumor mouse models. Finally, the difference in cytotoxic potential between WT and G-CSFR−/− macrophages was examined both in vitro and in vivo. Our results indicate that G-CSF promotes increased IL-10 production and decreased IL-12 production, which was reversed in G-CSFR−/− macrophages for a pro-inflammatory phenotype. Furthermore, G-CSFR−/− macrophages were characterized by higher levels of NOS2 expression and NO production, which led to greater tumor related cytotoxicity both in vitro and in vivo. Our results suggest that in the absence of G-CSFR, macrophage-related tumor cytotoxicity was amplified. These findings, along with our previous reports, pinpoint G-CSF /G-CSFR as a prominent target for possible clinical applications that aim to control the TME and the GI tumor progression.

scholarly journals Serum Amyloid A1 Induces Classically Activated Macrophages: A Role for Enhanced Fibril Formation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ann-Kathrin Gaiser ◽  
Shanna Bauer ◽  
Stephanie Ruez ◽  
Karlheinz Holzmann ◽  
Marcus Fändrich ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Intervention Strategy ◽  
Serum Amyloid ◽  
Macrophage Phenotype ◽  
Aa Amyloidosis ◽  
Inflammatory Conditions ◽  
Serum Amyloid A1 ◽  
And Function

AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo, macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.

scholarly journals The chemokine GROβ mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 860-869 ◽  
Author(s):  
Seiji Fukuda ◽  
Huimin Bian ◽  
Andrew G. King ◽  
Louis M. Pelus
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
And Function ◽  
Stimulating Factor ◽  
Cxcr4 Axis

Abstract Mobilized peripheral blood hematopoietic stem cells (PBSCs) demonstrate accelerated engraftment compared with bone marrow; however, mechanisms responsible for enhanced engraftment remain unknown. PBSCs mobilized by GROβ (GROβΔ4/CXCL2Δ4) or the combination of GROβΔ4 plus granulocyte colony-stimulating factor (G-CSF) restore neutrophil and platelet recovery faster than G-CSF–mobilized PBSCs. To determine mechanisms responsible for faster hematopoietic recovery, we characterized immunophenotype and function of the GROβ-mobilized grafts. PBSCs mobilized by GROβΔ4 alone or with G-CSF contained significantly more Sca-1+-c-kit+-lineage− (SKL) cells and more primitive CD34−-SKL cells compared with cells mobilized by G-CSF and demonstrated superior competitive long-term repopulation activity, which continued to increase in secondary and tertiary recipients. GROβΔ4-mobilized SKL cells adhered better to VCAM-1+ endothelial cells compared with G-CSF–mobilized cells. GROβΔ4-mobilized PBSCs did not migrate well to the chemokine stromal derived factor (SDF)-1α in vitro that was associated with higher CD26 expression. However, GROβΔ4-mobilized SKL and c-Kit+ lineage− (KL) cells homed more efficiently to marrow in vivo, which was not affected by selective CXCR4 and CD26 antagonists. These data suggest that GROβΔ4-mobilized PBSCs are superior in reconstituting long-term hematopoiesis, which results from differential mobilization of early stem cells with enhanced homing and long-term repopulating capacity. In addition, homing and engraftment of GROβΔ4-mobilized cells is less dependent on the SDF-1α/CXCR4 axis.

scholarly journals Changes in Cell Vitality, Phenotype, and Function of Dromedary Camel Leukocytes After Whole Blood Exposure to Heat Stress in vitro

2021 ◽  
Vol 8 ◽  
Author(s):  
Jamal Hussen
Keyword(s):  
Heat Stress ◽  
Adhesion Molecules ◽  
Mhc Class Ii ◽  
Whole Blood ◽  
Dromedary Camel ◽  
Macrophage Phenotype ◽  
Cell Vitality ◽  
And Function

The dromedary camel (Camelus dromedarius) is well-adapted to the desert environment with the ability to tolerate increased internal body temperatures rising daily to 41–42°C during extreme hot. This study was undertaken to assess whether in vitro incubation of camel blood at 41°C, simulating conditions of heat stress, differently alters cell vitality, phenotype, and function of leukocytes, compared to incubation at 37°C (normothermia). Using flow cytometry, the cell vitality (necrosis and apoptosis), the expression of several cell markers and adhesion molecules, and the antimicrobial functions of camel leukocytes were analyzed in vitro. The fraction of apoptotic cells within the granulocytes, lymphocytes, and monocytes increased significantly after incubation of camel whole blood at 41°C for 4 h. The higher increase in apoptotic granulocytes and monocytes compared to lymphocytes suggests higher resistance of camel lymphocytes to heat stress. Functionally, incubation of camel blood at 41°C for 4 h enhanced the phagocytosis and ROS production activities of camel neutrophils and monocytes toward S. aureus. Monocytes from camel blood incubated at 41°C for 4 h significantly decreased their expression level of MHC class II molecules with no change in the abundance of CD163, resulting in a CD163high MHC-IIlow M2-like macrophage phenotype. In addition, heat stress treatment showed an inhibitory effect on the LPS-induced changes in camel monocytes phenotype. Furthermore, in vitro incubation of camel blood at 41°C reduced the expression of the cell adhesion molecules CD18 and CD11a on neutrophils and monocytes. Collectively, the present study identified some heat-stress-induced phenotypic and functional alterations in camel blood leukocytes, providing a paradigm for comparative immunology in the large animals. The clinical relevance of the observed changes in camel leukocytes for the adaptation of the camel immune response to heat stress conditions needs further in vitro and in vivo studies.

scholarly journals Macrophage proliferation machinery leads to PDAC progression, but susceptibility to innate immunotherapy.

2021 ◽  
Author(s):  
David G DeNardo ◽  
Chong Zuo ◽  
John M. Baer ◽  
Brett L. Knolhoff ◽  
Jad I. Belle ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Genetically Engineered ◽  
Macrophage Phenotype ◽  
Sequencing Data ◽  
In Vitro Systems ◽  
Regulation Of Cell Cycle ◽  
The Impact

Tumor-associated macrophages (TAMs) are involved in many aspects of cancer progression and correlate with poor clinical outcomes in many cancer types, including pancreatic ductal adenocarcinomas (PDACs). Previous studies have shown that TAMs can populate PDAC tumors not only by monocyte recruitment but also by local proliferation. However, the impact local proliferation might have on macrophage phenotype and cancer progression is unknown. Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro systems to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also drive response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.

scholarly journals The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for proper mitochondrial function

2019 ◽  
Author(s):  
Hao Chen ◽  
Zhennan Shi ◽  
Jiaojiao Guo ◽  
Kao-jung Chang ◽  
Qianqian Chen ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Small Subunit ◽  
12S Rrna ◽  
Mitochondrial Rna ◽  
Protein Coding ◽  
Mitochondrial Ribosome ◽  
The Difference ◽  
And Function

ABSTRACTMitochondrial DNA (mtDNA) gene expression is coordinately regulated pre- and post-transcriptionally, and its perturbation can lead to human pathologies. Mitochondrial ribosomal RNAs (mt-rRNAs) undergo a series of nucleotide modifications following release from polycistronic mitochondrial RNA (mtRNA) precursors, which is essential for mitochondrial ribosomal biogenesis. Cytosine N4 methylation (m4C) at position 839 of the 12S small subunit (SSU) mt-rRNA was identified decades ago, however, its biogenesis and function have not been elucidated in details. Here we demonstrate that human Methyltransferase Like 15 (METTL15) is responsible for 12S mt-rRNA methylation at C839 (m4C839) both in vivo and in vitro. We tracked the evolutionary history of RNA m4C methyltransferases and revealed the difference in substrates preference between METTL15 and its bacterial ortholog rsmH. Additionally, unlike the very modest impact on ribosome upon loss of m4C methylation in bacterial SSU rRNA, we found that depletion of METTL15 specifically causes severe defects in mitochondrial ribosome assembly, which leads to an impaired translation of mitochondrial protein-coding genes and a decreased mitochondrial respiration capacity. Our findings point to a co-evolution of methylatransferase specificities and modification patterns in rRNA with differential impact on prokaryotic ribosome versus eukaryotic mitochondrial ribosome.

Increased dendritic cell number and function following continuous in vivo infusion of granulocyte macrophage–colony-stimulating factor and interleukin-4

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2869-2879 ◽  
Author(s):  
Saroj K. Basak ◽  
Airi Harui ◽  
Marina Stolina ◽  
Sherven Sharma ◽  
Kohnosuke Mitani ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Interleukin 4 ◽  
White Pulp ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
And Function ◽  
Stimulating Factor

Abstract Dendritic cells (DCs) are rare antigen-presenting cells that play a central role in stimulating immune responses. The combination of recombinant granulocyte macrophage–colony-stimulating factor (rGM-CSF) and recombinant interleukin-4 (rIL-4) provides an important stimulus for generating DCs from murine bone marrow precursors in vitro. Using miniature osmotic pumps, we now demonstrate that continuous infusion of these cytokines for 7 days had a similar effect in vivo, increasing the number and function of splenic DCs. Administration of rGM-CSF/rIL-4 (10 μg/d each) increased the concentration of CD11+ DCs by 2.7-fold and the absolute number of splenic DCs by an average of 5.7-fold. DC number also increased in peripheral blood and lymph nodes. The resultant DCs exhibited a different phenotype and function than those in control mice or mice treated with rGM-CSF alone. rGM-CSF/IL-4 increased both the myeloid (CD11c+/CD11b+) and the lymphoid (CD11c+/CD8α+) subpopulations, whereas rGM-CSF increased only myeloid DCs. DCs were highly concentrated in the T-cell areas of white pulp after rGM-CSF/IL-4 administration, whereas they were diffusely distributed throughout white pulp, marginal zones, and red pulp in mice treated with rGM-CSF alone. rGM-CSF/rIL-4 also significantly increased the expression of major histocompatibility complex (MHC) class I and MHC class II on CD11c+ cells and increased their capacity to take up antigens by macropinocytosis and receptor-mediated endocytosis. Splenic DCs generated in response to rGM-CSF/rIL-4 were functionally immature in terms of allostimulatory activity, but this activity increased after short-term in vitro culture. Systemic treatment with rGM-CSF/rIL-4 enhanced the response to an adenoviral-based vaccine and led to antigen-specific retardation in the growth of established tumor. We conclude that systemic therapy with the combination of rGM-CSF/rIL-4 provides a new approach for generating DCs in vivo.

scholarly journals Acidity promotes tumor progression by altering macrophage phenotype in prostate cancer

2018 ◽  
Author(s):  
Asmaa El-Kenawi ◽  
Chandler Gatenbee ◽  
Mark Robertson-Tessi ◽  
Rafael Bravo ◽  
Jasreman Dhillon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Progression ◽  
In Silico ◽  
Macrophage Phenotype ◽  
Extracellular Acidification ◽  
Environmental Signals ◽  
Prostate Carcinogenesis ◽  
Tumor Phenotype

Tumors rapidly ferment glucose to lactic acid even in the presence of oxygen, and coupling high glycolysis with poor perfusion leads to extracellular acidification. Here we demonstrate that acidity, independent from lactate, augments the pro-tumor phenotype of macrophages. We used zwitterionic buffers to show that activating macrophages at pH 6.8 in vitro enhanced an IL-4-driven phenotype as measured by gene expression, cytokine profiling, and functional assays. These results were recapitulated in vivo wherein neutralizing intratumoral acidity reduced the pro-tumor phenotype of macrophages, while also decreasing tumor incidence and invasion in the TRAMP model of prostate cancer. These results were recapitulated using an in silico mathematical model that simulate macrophage responses to environmental signals. By turning off acid-induced cellular responses, our in silico mathematical modeling shows that acid-resistant macrophages can limit tumor progression. In summary, this study suggests that tumor acidity contributes to prostate carcinogenesis by altering the state of macrophage activation.

scholarly journals Resolution of Sterile Inflammation: Role for Vitamin C

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Bassem M. Mohammed ◽  
Bernard J. Fisher ◽  
Quoc K. Huynh ◽  
Dayanjan S. Wijesinghe ◽  
Charles E. Chalfant ◽  
...  
Keyword(s):  
Vitamin C ◽  
Sterile Inflammation ◽  
Macrophage Phenotype ◽  
Proinflammatory Response ◽  
Resolution Of Inflammation ◽  
Human Sepsis ◽  
And Function ◽  
Deficient Mice

Introduction. Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited.Methods. To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages.Results. VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response toin vitroLPS stimulation. VitC sufficiency andin vivoVitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses.Conclusion. VitC sufficiency favorably modulates macrophage function.In vivoorin vitroVitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.

scholarly journals GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

2020 ◽  
Author(s):  
Christopher Y Itoh ◽  
Cal Gunnarsson ◽  
Gregory H Babunovic ◽  
Armel Nibasumba ◽  
Ngomu Akeem Akilimali ◽  
...  
Keyword(s):  
Experimental Approach ◽  
Dominant Role ◽  
Human Monocyte ◽  
Transcriptional Networks ◽  
Gm Csf ◽  
Oxidative Signaling ◽  
Inflammatory Phenotype ◽  
And Function

AbstractMacrophages are central mediators of immunity that integrate diverse signals derived from differentiation cues, tissue location, and disease. Controlling macrophage state and function is an appealing therapeutic objective across many diseases including cancer, atherosclerosis, and tuberculosis. Despite the growing appreciation for the in vivo complexity of macrophage state, existing in vitro models of human monocyte-derived macrophages have used a limited number of individual perturbations to explore the complex phenotypic space that macrophages can occupy. Here, we leverage a tiered differentiation, activation, and stimulation strategy to generate libraries of in vitro monocyte-derived macrophages and examine the in vitro state space of macrophage function using high-dimensional technologies. Our tiered experimental approach further revealed a striking relationship between GM-CSF differentiation and IL-10 production. Cells that were differentiated with GM-CSF produced very low or undetectable levels of IL-10 independent of activation or stimulation condition. To nominate candidate regulators of this IL-10 response, we leverage unbiased single-cell mRNA sequencing to identify transcriptional networks associated with GM-CSF-derived cells. Using these data, we identify oxidative signaling pathways as upregulated in GM-CSF derived cells and demonstrate that scavenging of oxidative radicals can enhance IL-10 production in these cells. Collectively, these data underscore the complexity of monocyte-derived macrophage state over time and highlight a dominant role for GM-CSF in tuning macrophage inflammatory phenotype, metabolic state, and plasticity.

Enhancement of ADP-induced Platelet Aggregation by Adrenaline in Vivo and Its Prevention

1973 ◽  
Vol 29 (02) ◽  
pp. 490-498 ◽  
Author(s):  
Hiroh Yamazaki ◽  
Itsuro Kobayashi ◽  
Tadahiro Sano ◽  
Takio Shimamoto
Keyword(s):  
Platelet Count ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
The Other ◽  
Endothelial Surface ◽  
Important Interaction ◽  
Blood Coagulability ◽  
The Difference

SummaryThe authors previously reported a transient decrease in adhesive platelet count and an enhancement of blood coagulability after administration of a small amount of adrenaline (0.1-1 µg per Kg, i. v.) in man and rabbit. In such circumstances, the sensitivity of platelets to aggregation induced by ADP was studied by an optical density method. Five minutes after i. v. injection of 1 µg per Kg of adrenaline in 10 rabbits, intensity of platelet aggregation increased to 115.1 ± 4.9% (mean ± S. E.) by 10∼5 molar, 121.8 ± 7.8% by 3 × 10-6 molar and 129.4 ± 12.8% of the value before the injection by 10”6 molar ADP. The difference was statistically significant (P<0.01-0.05). The above change was not observed in each group of rabbits injected with saline, 1 µg per Kg of 1-noradrenaline or 0.1 and 10 µg per Kg of adrenaline. Also, it was prevented by oral administration of 10 mg per Kg of phenoxybenzamine or propranolol or aspirin or pyridinolcarbamate 3 hours before the challenge. On the other hand, the enhancement of ADP-induced platelet aggregation was not observed in vitro, when 10-5 or 3 × 10-6 molar and 129.4 ± 12.8% of the value before 10∼6 molar ADP was added to citrated platelet rich plasma (CPRP) of rabbit after incubation at 37°C for 30 second with 0.01, 0.1, 1, 10 or 100 µg per ml of adrenaline or noradrenaline. These results suggest an important interaction between endothelial surface and platelets in connection with the enhancement of ADP-induced platelet aggregation by adrenaline in vivo.

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