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Myeloid-Derived Suppressor Cells and Pulmonary Hypertension.
Bryant AJ, Mehrad B, Brusko TM, West JD, Moldawer LL
(2018) Int J Mol Sci 19:
MeSH Terms: Animals, Dendritic Cells, Humans, Hypertension, Pulmonary, Myeloid-Derived Suppressor Cells, Receptors, Interleukin-8B, Signal Transduction
Show Abstract · Added April 2, 2019
Myeloid⁻derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow⁻derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.
0 Communities
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MeSH Terms
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F
(2018) Cell Host Microbe 23: 203-214.e5
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Bacterial Toxins, Bacteroides fragilis, Carcinogenesis, Cell Line, Tumor, Colon, Colorectal Neoplasms, Enzyme Activation, Epithelial Cells, Female, Gene Deletion, HT29 Cells, Humans, Inflammation, Interleukin-17, Male, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Receptors, Interleukin-17, Receptors, Interleukin-8B, STAT3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 20, 2018
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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26 MeSH Terms
The role of MyD88- and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes.
Hernandez A, Bohannon JK, Luan L, Fensterheim BA, Guo Y, Patil NK, McAdams C, Wang J, Sherwood ER
(2016) J Leukoc Biol 100: 1311-1322
MeSH Terms: Adaptor Proteins, Vesicular Transport, Animals, CD11b Antigen, Chemokine CXCL1, Chemokine CXCL2, Chemotaxis, Leukocyte, Granulocyte Colony-Stimulating Factor, Immunity, Innate, L-Selectin, Lipid A, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Myeloid Differentiation Factor 88, Myelopoiesis, Neutrophils, Receptors, Interleukin-8B, Signal Transduction, Toll-Like Receptor 4
Show Abstract · Added December 13, 2016
Treatment with the TLR4 agonist MPLA augments innate resistance to common bacterial pathogens. However, the cellular and molecular mechanisms by which MPLA augments innate immunocyte functions are not well characterized. This study examined the importance of MyD88- and TRIF-dependent signaling for leukocyte mobilization, recruitment, and activation following administration of MPLA. MPLA potently induced MyD88- and TRIF-dependent signaling. A single injection of MPLA caused rapid mobilization and recruitment of neutrophils, a response that was largely mediated by the chemokines CXCL1 and -2 and the hemopoietic factor G-CSF. Rapid neutrophil recruitment and chemokine production were regulated by both pathways although the MyD88-dependent pathway showed some predominance. In further studies, multiple injections of MPLA potently induced mobilization and recruitment of neutrophils and monocytes. Neutrophil recruitment after multiple injections of MPLA was reliant on MyD88-dependent signaling, but effective monocyte recruitment required activation of both pathways. MPLA treatment induced expansion of myeloid progenitors in bone marrow and upregulation of CD11b and shedding of L-selectin by neutrophils, all of which were attenuated in MyD88- and TRIF-deficient mice. These results show that MPLA-induced neutrophil and monocyte recruitment, expansion of bone marrow progenitors and augmentation of neutrophil adhesion molecule expression are regulated by both the MyD88- and TRIF-dependent pathways.
© Society for Leukocyte Biology.
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1 Members
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21 MeSH Terms
Adaptor protein2 (AP2) orchestrates CXCR2-mediated cell migration.
Raman D, Sai J, Hawkins O, Richmond A
(2014) Traffic 15: 451-69
MeSH Terms: Adaptor Protein Complex 2, Base Sequence, Chemotaxis, DNA Primers, Endocytosis, HEK293 Cells, HL-60 Cells, Humans, Mutagenesis, Site-Directed, Receptors, Interleukin-8B
Show Abstract · Added January 30, 2014
The chemokine receptor CXCR2 is vital for inflammation, wound healing, angiogenesis, cancer progression and metastasis. Adaptor protein 2 (AP2), a clathrin binding heterotetrameric protein comprised of α, β2, μ2 and σ2 subunits, facilitates clathrin-mediated endocytosis. Mutation of the LLKIL motif in the CXCR2 carboxyl-terminal domain (CTD) results in loss of AP2 binding to the receptor and loss of ligand-mediated receptor internalization and chemotaxis. AP2 knockdown also results in diminished ligand-mediated CXCR2 internalization, polarization and chemotaxis. Using knockdown/rescue approaches with AP2-μ2 mutants, the binding domains were characterized in reference to CXCR2 internalization and chemotaxis. When in an open conformation, μ2 Patch 1 and Patch 2 domains bind tightly to membrane PIP2 phospholipids. When AP2-μ2, is replaced with μ2 mutated in Patch 1 and/or Patch 2 domains, ligand-mediated receptor binding and internalization are not lost. However, chemotaxis requires AP2-μ2 Patch 1, but not Patch 2. AP2-σ2 has been demonstrated to bind dileucine motifs to facilitate internalization. Expression of AP2-σ2 V88D and V98S dominant negative mutants resulted in loss of CXCR2 mediated chemotaxis. Thus, AP2 binding to both membrane phosphatidylinositol phospholipids and dileucine motifs is crucial for directional migration or chemotaxis. Moreover, AP2-mediated receptor internalization can be dissociated from AP2-mediated chemotaxis.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
2 Communities
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2 Resources
10 MeSH Terms
CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways.
Sobolik T, Su YJ, Wells S, Ayers GD, Cook RS, Richmond A
(2014) Mol Biol Cell 25: 566-82
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, HEK293 Cells, HL-60 Cells, Humans, Lymph Nodes, MAP Kinase Signaling System, MCF-7 Cells, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphatidylinositol Phosphates, Receptors, CXCR4, Receptors, Interleukin-8B, Signal Transduction, Up-Regulation
Show Abstract · Added March 14, 2014
Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box-binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte-macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.
2 Communities
4 Members
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25 MeSH Terms
Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection.
Reyes-Robles T, Alonzo F, Kozhaya L, Lacy DB, Unutmaz D, Torres VJ
(2013) Cell Host Microbe 14: 453-9
MeSH Terms: Animals, Bacterial Proteins, Cell Survival, Disease Models, Animal, Exotoxins, Host-Pathogen Interactions, Humans, Mice, Monocytes, Neutrophils, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Staphylococcal Infections, Staphylococcus aureus, Survival Analysis, Virulence
Show Abstract · Added May 29, 2014
The Staphylococcus aureus leukotoxin ED (LukED) is a pore-forming toxin required for the lethality associated with bacteremia in murine models. LukED targets the chemokine receptor CCR5 to kill T lymphocytes, macrophages, and dendritic cells. LukED also kills CCR5-deficient cells, like neutrophils, suggesting the existence of additional cellular receptors. Here, we identify the chemokine receptors CXCR1 and CXCR2 as the targets of LukED on neutrophils. The LukE subunit binds neutrophils in a specific and saturable manner, and this interaction is inhibited by CXCL8, the high-affinity endogenous ligand of CXCR1 and CXCR2. LukED recognition of CXCR1 and CXCR2 promotes the killing of monocytes and neutrophils in vitro. LukED-mediated targeting of CXCR1 and CXCR2(+) cells contributes to S. aureus pathogenesis and facilitates lethality in systemically infected mice. Thus, LukED is a versatile toxin that endows S. aureus with the ability to simultaneously disarm both innate and adaptive compartments of the host immune response.
Copyright © 2013 Elsevier Inc. All rights reserved.
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16 MeSH Terms
The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions.
Raghuwanshi SK, Su Y, Singh V, Haynes K, Richmond A, Richardson RM
(2012) J Immunol 189: 2824-32
MeSH Terms: Animals, Cell Line, Tumor, Exocytosis, Female, G-Protein-Coupled Receptor Kinase 2, G-Protein-Coupled Receptor Kinases, Humans, Interleukin-8, Leukemia, Basophilic, Acute, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neovascularization, Physiologic, Neutrophils, Phosphorylation, Rats, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Signal Transduction
Show Abstract · Added May 31, 2013
The chemokine receptors, CXCR1 and CXCR2, couple to Gαi to induce leukocyte recruitment and activation at sites of inflammation. Upon activation by CXCL8, these receptors become phosphorylated, desensitized, and internalized. In this study, we investigated the role of different G protein-coupled receptor kinases (GRKs) in CXCR1- and CXCR2-mediated cellular functions. To that end, short hairpin RNA was used to inhibit GRK2, 3, 5, and 6 in RBL-2H3 cells stably expressing CXCR1 or CXCR2, and CXCL8-mediated receptor activation and regulation were assessed. Inhibition of GRK2 and GRK6 increased CXCR1 and CXCR2 resistance to phosphorylation, desensitization, and internalization, respectively, and enhanced CXCL8-induced phosphoinositide hydrolysis and exocytosis in vitro. GRK2 depletion diminished CXCR1-induced ERK1/2 phosphorylation but had no effect on CXCR2-induced ERK1/2 phosphorylation. GRK6 depletion had no significant effect on CXCR1 function. However, peritoneal neutrophils from mice deficient in GRK6 (GRK6(-/-)) displayed an increase in CXCR2-mediated G protein activation but in vitro exhibited a decrease in chemotaxis, receptor desensitization, and internalization relative to wild-type (GRK6(+/+)) cells. In contrast, neutrophil recruitment in vivo in GRK6(-/-) mice was increased in response to delivery of CXCL1 through the air pouch model. In a wound-closure assay, GRK6(-/-) mice showed enhanced myeloperoxidase activity, suggesting enhanced neutrophil recruitment, and faster wound closure compared with GRK6(+/+) animals. Taken together, the results indicate that CXCR1 and CXCR2 couple to distinct GRK isoforms to mediate and regulate inflammatory responses. CXCR1 predominantly couples to GRK2, whereas CXCR2 interacts with GRK6 to negatively regulate receptor sensitization and trafficking, thus affecting cell signaling and angiogenesis.
2 Communities
1 Members
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20 MeSH Terms
Abnormal spontaneous interleukin 8 receptor expression: a brief report of two cases.
Antas P, Holland S, Sterling T
(2012) Rev Soc Bras Med Trop 45: 134-7
MeSH Terms: Case-Control Studies, Cohort Studies, Flow Cytometry, Humans, Latent Tuberculosis, Male, Middle Aged, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Tuberculosis
Show Abstract · Added May 29, 2014
Interleukin 8 (CXCL8) is an autocrine chemokine specific for the chemoattraction and activation of granulocytes, NKT cells and T lymphocytes. Patients with tuberculosis and latent Mycobacterium tuberculosis infection were assessed for the spontaneous expression of CXCR1 (CD128) and CXCR2 on lymphocytes and monocytes. Compared with ex vivo profiles, increased spontaneous CXCR2 expression and normal CXCR1 expression were found on lymphocytes in two out of 59 individuals. Monocytes showed normal ex vivo profiles for both receptors. After stimulation with purified protein derivative, the in vitro levels of CXCL8 were below the median levels of all patients with prior tuberculosis. Spontaneous CXCR2 modulation did not cause notable variation in the in vitro levels of CXCL8.
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10 MeSH Terms
Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice.
Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM, Zhang P, Guttentag SH, Kolls JK, Oliver PM, Bushman FD, Worthen GS
(2012) J Clin Invest 122: 974-86
MeSH Terms: Animals, Cell Separation, Chemokine CXCL5, Flow Cytometry, Gene Expression Regulation, Granulocyte Colony-Stimulating Factor, Homeostasis, Interleukin-17, Intestinal Mucosa, Lung, Mice, Mice, Transgenic, Models, Biological, Neutrophils, Phenotype, Receptors, Interleukin-8B
Show Abstract · Added January 20, 2015
Neutrophils are essential for maintaining innate immune surveillance under normal conditions, but also represent a major contributor to tissue damage during inflammation. Neutrophil homeostasis is therefore tightly regulated. Cxcr2 plays a critical role in neutrophil homeostasis, as Cxcr2(-/-) mice demonstrate mild neutrophilia and severe neutrophil hyperplasia in the bone marrow. The mechanisms underlying these phenotypes, however, are unclear. We report here that Cxcr2 on murine neutrophils inhibits the IL-17A/G-CSF axis that regulates neutrophil homeostasis. Furthermore, enterocyte-derived Cxcl5 in the gut regulates IL-17/G-CSF levels and contributes to Cxcr2-dependent neutrophil homeostasis. Conversely, G-CSF was required for Cxcl5-dependent regulation of neutrophil homeostasis, and inhibition of IL-17A reduced plasma G-CSF concentrations and marrow neutrophil numbers in both Cxcl5(-/-) and Cxcr2(-/-) mice. Cxcr2(-/-) mice constitutively expressed IL-17A and showed increased numbers of IL-17A-producing cells in the lung, terminal ileum, and spleen. Most IL-17-producing splenocytes were responsive to IL-1β plus IL-23 in vitro. Depletion of commensal microbes by antibiotic treatment in Cxcr2(-/-) mice markedly decreased IL-17A and G-CSF expression, neutrophilia, and marrow myeloid hyperplasia. These data suggest a critical role for Cxcr2, Cxcl5, and commensal bacteria in regulation of the IL-17/G-CSF axis and neutrophil homeostasis at mucosal sites and have implications for the development of treatments for pathologies resulting from either excessive or ineffective neutrophil responses.
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16 MeSH Terms
Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma.
Ijichi H, Chytil A, Gorska AE, Aakre ME, Bierie B, Tada M, Mohri D, Miyabayashi K, Asaoka Y, Maeda S, Ikenoue T, Tateishi K, Wright CV, Koike K, Omata M, Moses HL
(2011) J Clin Invest 121: 4106-17
MeSH Terms: Animals, Carcinoma, Pancreatic Ductal, Chemokines, CXC, Connective Tissue Growth Factor, Female, Gene Expression, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Pancreatic Neoplasms, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins p21(ras), Receptor, Transforming Growth Factor-beta Type II, Receptors, Interleukin-8B, Receptors, Transforming Growth Factor beta, Signal Transduction, Stromal Cells, Tumor Microenvironment
Show Abstract · Added March 10, 2014
Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.
3 Communities
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20 MeSH Terms