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Interpreting an apoptotic corpse as anti-inflammatory involves a chloride sensing pathway.
Perry JSA, Morioka S, Medina CB, Iker Etchegaray J, Barron B, Raymond MH, Lucas CD, Onengut-Gumuscu S, Delpire E, Ravichandran KS
(2019) Nat Cell Biol 21: 1532-1543
MeSH Terms: Animals, Apoptosis, Biological Transport, Cell Line, Cell Line, Tumor, Chlorides, Humans, Inflammation, Jurkat Cells, Mice, Mice, Inbred C57BL, Oxidative Stress, Phagocytes, Phagocytosis, Signal Transduction, Sodium-Potassium-Chloride Symporters, Transcription, Genetic
Show Abstract · Added March 18, 2020
Apoptotic cell clearance (efferocytosis) elicits an anti-inflammatory response by phagocytes, but the mechanisms that underlie this response are still being defined. Here, we uncover a chloride-sensing signalling pathway that controls both the phagocyte 'appetite' and its anti-inflammatory response. Efferocytosis transcriptionally altered the genes that encode the solute carrier (SLC) proteins SLC12A2 and SLC12A4. Interfering with SLC12A2 expression or function resulted in a significant increase in apoptotic corpse uptake per phagocyte, whereas the loss of SLC12A4 inhibited corpse uptake. In SLC12A2-deficient phagocytes, the canonical anti-inflammatory program was replaced by pro-inflammatory and oxidative-stress-associated gene programs. This 'switch' to pro-inflammatory sensing of apoptotic cells resulted from the disruption of the chloride-sensing pathway (and not due to corpse overload or poor degradation), including the chloride-sensing kinases WNK1, OSR1 and SPAK-which function upstream of SLC12A2-had a similar effect on efferocytosis. Collectively, the WNK1-OSR1-SPAK-SLC12A2/SLC12A4 chloride-sensing pathway and chloride flux in phagocytes are key modifiers of the manner in which phagocytes interpret the engulfed apoptotic corpse.
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Bacterial Energetic Requirements for Helicobacter pylori Cag Type IV Secretion System-Dependent Alterations in Gastric Epithelial Cells.
Lin AS, Dooyema SDR, Frick-Cheng AE, Harvey ML, Suarez G, Loh JT, McDonald WH, McClain MS, Peek RM, Cover TL
(2020) Infect Immun 88:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Biological Transport, DNA, Bacterial, Epithelial Cells, Helicobacter pylori, Humans, Interleukin-8, Lipopolysaccharides, NF-kappa B, Peptidoglycan, Toll-Like Receptor 9, Type IV Secretion Systems, Virulence Factors
Show Abstract · Added March 3, 2020
colonizes the stomach in about half of the world's population. strains containing the pathogenicity island ( PAI) are associated with a higher risk of gastric adenocarcinoma or peptic ulcer disease than PAI-negative strains. The PAI encodes a type IV secretion system (T4SS) that mediates delivery of the CagA effector protein as well as nonprotein bacterial constituents into gastric epithelial cells. -induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interleukin-8 (IL-8) secretion are attributed to T4SS-dependent delivery of lipopolysaccharide metabolites and peptidoglycan into host cells, and Toll-like receptor 9 (TLR9) activation is attributed to delivery of bacterial DNA. In this study, we analyzed the bacterial energetic requirements associated with these cellular alterations. Mutant strains lacking Cagα, Cagβ, or CagE (putative ATPases corresponding to VirB11, VirD4, and VirB4 in prototypical T4SSs) were capable of T4SS core complex assembly but defective in CagA translocation into host cells. Thus, the three Cag ATPases are not functionally redundant. Cagα and CagE were required for -induced NF-κB activation, IL-8 secretion, and TLR9 activation, but Cagβ was dispensable for these responses. We identified putative ATP-binding motifs (Walker-A and Walker-B) in each of the ATPases and generated mutant strains in which these motifs were altered. Each of the Walker box mutant strains exhibited properties identical to those of the corresponding deletion mutant strains. These data suggest that Cag T4SS-dependent delivery of nonprotein bacterial constituents into host cells occurs through mechanisms different from those used for recruitment and delivery of CagA into host cells.
Copyright © 2020 American Society for Microbiology.
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The Extracellular Matrix Receptor Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus.
Chiusa M, Hu W, Liao HJ, Su Y, Borza CM, de Caestecker MP, Skrypnyk NI, Fogo AB, Pedchenko V, Li X, Zhang MZ, Hudson BG, Basak T, Vanacore RM, Zent R, Pozzi A
(2019) J Am Soc Nephrol 30: 1605-1624
MeSH Terms: Actins, Acute Kidney Injury, Animals, Biological Transport, Cell Line, Cell Nucleus, Chromatin, Collagen Type I, Collagen Type IV, Discoidin Domain Receptor 1, Humans, Kidney Tubules, Proximal, Male, Mice, Myosin Heavy Chains, Nuclear Localization Signals, Retinoblastoma-Binding Protein 4, SEC Translocation Channels, Transcription, Genetic
Show Abstract · Added May 10, 2020
BACKGROUND - The discoidin domain receptor 1 (DDR1) is activated by collagens, upregulated in injured and fibrotic kidneys, and contributes to fibrosis by regulating extracellular matrix production, but how DDR1 controls fibrosis is poorly understood. DDR1 is a receptor tyrosine kinase (RTK). RTKs can translocate to the nucleus a nuclear localization sequence (NLS) present on the receptor itself or a ligand it is bound to. In the nucleus, RTKs regulate gene expression by binding chromatin directly or by interacting with transcription factors.
METHODS - To determine whether DDR1 translocates to the nucleus and whether this event is mediated by collagen-induced DDR1 activation, we generated renal cells expressing wild-type or mutant forms of DDR1 no longer able to bind collagen. Then, we determined the location of the DDR1 upon collagen stimulation. Using both biochemical assays and immunofluorescence, we analyzed the steps involved in DDR1 nuclear translocation.
RESULTS - We show that although DDR1 and its natural ligand, collagen, lack an NLS, DDR1 is present in the nucleus of injured human and mouse kidney proximal tubules. We show that DDR1 nuclear translocation requires collagen-mediated receptor activation and interaction of DDR1 with SEC61B, a component of the Sec61 translocon, and nonmuscle myosin IIA and -actin. Once in the nucleus, DDR1 binds to chromatin to increase the transcription of collagen IV, a major collagen upregulated in fibrosis.
CONCLUSIONS - These findings reveal a novel mechanism whereby activated DDR1 translates to the nucleus to regulate synthesis of profibrotic molecules.
Copyright © 2019 by the American Society of Nephrology.
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AXL Mediates Esophageal Adenocarcinoma Cell Invasion through Regulation of Extracellular Acidification and Lysosome Trafficking.
Maacha S, Hong J, von Lersner A, Zijlstra A, Belkhiri A
(2018) Neoplasia 20: 1008-1022
MeSH Terms: Adenocarcinoma, Animals, Benzocycloheptenes, Biological Transport, Cathepsin B, Cell Line, Tumor, Chick Embryo, Chorioallantoic Membrane, Epithelial-Mesenchymal Transition, Esophageal Neoplasms, Gene Expression Regulation, Neoplastic, Humans, Hydrogen-Ion Concentration, Lactates, Lysosomes, Monocarboxylic Acid Transporters, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Symporters, Triazoles
Show Abstract · Added April 10, 2019
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that is characterized by resistance to chemotherapy and a poor clinical outcome. The overexpression of the receptor tyrosine kinase AXL is frequently associated with unfavorable prognosis in EAC. Although it is well documented that AXL mediates cancer cell invasion as a downstream effector of epithelial-to-mesenchymal transition, the precise molecular mechanism underlying this process is not completely understood. Herein, we demonstrate for the first time that AXL mediates cell invasion through the regulation of lysosomes peripheral distribution and cathepsin B secretion in EAC cell lines. Furthermore, we show that AXL-dependent peripheral distribution of lysosomes and cell invasion are mediated by extracellular acidification, which is potentiated by AXL-induced secretion of lactate through AKT-NF-κB-dependent MCT-1 regulation. Our novel mechanistic findings support future clinical studies to evaluate the therapeutic potential of the AXL inhibitor R428 (BGB324) in highly invasive EAC.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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Acute Nitric Oxide Synthase Inhibition Accelerates Transendothelial Insulin Efflux In Vivo.
Williams IM, McClatchey PM, Bracy DP, Valenzuela FA, Wasserman DH
(2018) Diabetes 67: 1962-1975
MeSH Terms: Animals, Biological Transport, Blood Pressure, Blotting, Western, Glucose, Insulin, Male, Mice, Inbred C57BL, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Transendothelial and Transepithelial Migration
Show Abstract · Added March 26, 2019
Before insulin can stimulate glucose uptake in muscle, it must be delivered to skeletal muscle (SkM) through the microvasculature. Insulin delivery is determined by SkM perfusion and the rate of movement of insulin across the capillary endothelium. The endothelium therefore plays a central role in regulating insulin access to SkM. Nitric oxide (NO) is a key regulator of endothelial function and stimulates arterial vasodilation, which increases SkM perfusion and the capillary surface area available for insulin exchange. The effects of NO on transendothelial insulin efflux (TIE), however, are unknown. We hypothesized that acute reduction of endothelial NO would reduce TIE. However, intravital imaging of TIE in mice revealed that reduction of NO by l--nitro-l-arginine methyl ester (l-NAME) enhanced the rate of TIE by ∼30% and increased total extravascular insulin delivery. This accelerated TIE was associated with more rapid insulin-stimulated glucose lowering. Sodium nitroprusside, an NO donor, had no effect on TIE in mice. The effects of l-NAME on TIE were not due to changes in blood pressure alone, as a direct-acting vasoconstrictor (phenylephrine) did not affect TIE. These results demonstrate that acute NO synthase inhibition increases the permeability of capillaries to insulin, leading to an increase in delivery of insulin to SkM.
© 2018 by the American Diabetes Association.
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Na -K -2Cl Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia.
Delpire E, Gagnon KB
(2018) Compr Physiol 8: 871-901
MeSH Terms: Animals, Biological Transport, Cell Membrane, Epithelial Cells, Gene Expression Regulation, Humans, Sodium-Potassium-Chloride Symporters, Structure-Activity Relationship
Show Abstract · Added April 2, 2019
Two genes encode the Na -K -2Cl cotransporters, NKCC1 and NKCC2, that mediate the tightly coupled movement of 1Na , 1K , and 2Cl across the plasma membrane of cells. Na -K -2Cl cotransport is driven by the chemical gradient of the three ionic species across the membrane, two of them maintained by the action of the Na /K pump. In many cells, NKCC1 accumulates Cl above its electrochemical potential equilibrium, thereby facilitating Cl channel-mediated membrane depolarization. In smooth muscle cells, this depolarization facilitates the opening of voltage-sensitive Ca channels, leading to Ca influx, and cell contraction. In immature neurons, the depolarization due to a GABA-mediated Cl conductance produces an excitatory rather than inhibitory response. In many cell types that have lost water, NKCC is activated to help the cells recover their volume. This is specially the case if the cells have also lost Cl . In combination with the Na /K pump, the NKCC's move ions across various specialized epithelia. NKCC1 is involved in Cl -driven fluid secretion in many exocrine glands, such as sweat, lacrimal, salivary, stomach, pancreas, and intestine. NKCC1 is also involved in K -driven fluid secretion in inner ear, and possibly in Na -driven fluid secretion in choroid plexus. In the thick ascending limb of Henle, NKCC2 activity in combination with the Na /K pump participates in reabsorbing 30% of the glomerular-filtered Na . Overall, many critical physiological functions are maintained by the activity of the two Na -K -2Cl cotransporters. In this overview article, we focus on the functional roles of the cotransporters in nonpolarized cells and in epithelia. © 2018 American Physiological Society. Compr Physiol 8:871-901, 2018.
Copyright © 2018 American Physiological Society. All rights reserved.
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8 MeSH Terms
Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca Sensitivity of Insulin Secretion Vesicles.
Huang C, Walker EM, Dadi PK, Hu R, Xu Y, Zhang W, Sanavia T, Mun J, Liu J, Nair GG, Tan HYA, Wang S, Magnuson MA, Stoeckert CJ, Hebrok M, Gannon M, Han W, Stein R, Jacobson DA, Gu G
(2018) Dev Cell 45: 347-361.e5
MeSH Terms: Animals, Biological Transport, Calcium, Cell Differentiation, Female, Gene Expression Regulation, Glucose, Humans, Hypoglycemic Agents, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Sweetening Agents, Synaptotagmins
Show Abstract · Added April 17, 2018
Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca concentrations, suggesting differences in the Ca sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca binding paralog of the β cell Ca sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca sensing plays in regulating β cell maturation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Chronic kidney disease alters lipid trafficking and inflammatory responses in macrophages: effects of liver X receptor agonism.
Kaseda R, Tsuchida Y, Yang HC, Yancey PG, Zhong J, Tao H, Bian A, Fogo AB, Linton MRF, Fazio S, Ikizler TA, Kon V
(2018) BMC Nephrol 19: 17
MeSH Terms: Adult, Aged, Biological Transport, Female, Humans, Hydrocarbons, Fluorinated, Inflammation Mediators, Lipoproteins, HDL, Lipoproteins, LDL, Liver X Receptors, Macrophages, Male, Middle Aged, Protein Transport, Renal Insufficiency, Chronic, Sulfonamides, THP-1 Cells
Show Abstract · Added April 10, 2018
BACKGROUND - Our aim was to evaluate lipid trafficking and inflammatory response of macrophages exposed to lipoproteins from subjects with moderate to severe chronic kidney disease (CKD), and to investigate the potential benefits of activating cellular cholesterol transporters via liver X receptor (LXR) agonism.
METHODS - LDL and HDL were isolated by sequential density gradient ultracentrifugation of plasma from patients with stage 3-4 CKD and individuals without kidney disease (HDL and HDL, respectively). Uptake of LDL, cholesterol efflux to HDL, and cellular inflammatory responses were assessed in human THP-1 cells. HDL effects on inflammatory markers (MCP-1, TNF-α, IL-1β), Toll-like receptors-2 (TLR-2) and - 4 (TLR-4), ATP-binding cassette class A transporter (ABCA1), NF-κB, extracellular signal regulated protein kinases 1/2 (ERK1/2) were assessed by RT-PCR and western blot before and after in vitro treatment with an LXR agonist.
RESULTS - There was no difference in macrophage uptake of LDL isolated from CKD versus controls. By contrast, HD was significantly less effective than HDL in accepting cholesterol from cholesterol-enriched macrophages (median 20.8% [IQR 16.1-23.7] vs control (26.5% [IQR 19.6-28.5]; p = 0.008). LXR agonist upregulated ABCA1 expression and increased cholesterol efflux to HDL of both normal and CKD subjects, although the latter continued to show lower efflux capacity. HDL increased macrophage cytokine response (TNF-α, MCP-1, IL-1β, and NF-κB) versus HDL. The heightened cytokine response to HDL was further amplified in cells treated with LXR agonist. The LXR-augmentation of inflammation was associated with increased TLR-2 and TLR-4 and ERK1/2.
CONCLUSIONS - Moderate to severe impairment in kidney function promotes foam cell formation that reflects impairment in cholesterol acceptor function of HDL. Activation of cellular cholesterol transporters by LXR agonism improves but does not normalize efflux to HDL. However, LXR agonism actually increases the pro-inflammatory effects of HDL through activation of TLRs and ERK1/2 pathways.
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17 MeSH Terms
Hepatocyte estrogen receptor alpha mediates estrogen action to promote reverse cholesterol transport during Western-type diet feeding.
Zhu L, Shi J, Luu TN, Neuman JC, Trefts E, Yu S, Palmisano BT, Wasserman DH, Linton MF, Stafford JM
(2018) Mol Metab 8: 106-116
MeSH Terms: Animals, Atherosclerosis, Biological Transport, Cells, Cultured, Cholesterol, Diet, Western, Estrogen Receptor alpha, Female, Hepatocytes, Insulin Resistance, Macrophages, Male, Mice, Mice, Inbred C57BL, Obesity, Sex Factors
Show Abstract · Added April 10, 2018
OBJECTIVE - Hepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported.
METHODS AND RESULTS - Using LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls.
CONCLUSIONS - Estrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet.
Published by Elsevier GmbH.
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Insulin exits skeletal muscle capillaries by fluid-phase transport.
Williams IM, Valenzuela FA, Kahl SD, Ramkrishna D, Mezo AR, Young JD, Wells KS, Wasserman DH
(2018) J Clin Invest 128: 699-714
MeSH Terms: Animals, Antigens, CD, Biological Transport, Capillaries, Diabetes Mellitus, Glucose, Glucose Clamp Technique, Humans, Hyperinsulinism, Image Processing, Computer-Assisted, Insulin, Intravital Microscopy, Kinetics, Male, Mice, Mice, Inbred C57BL, Models, Theoretical, Muscle, Skeletal, Protein Binding, Receptor, Insulin, Rhodamines
Show Abstract · Added March 14, 2018
Before insulin can stimulate myocytes to take up glucose, it must first move from the circulation to the interstitial space. The continuous endothelium of skeletal muscle (SkM) capillaries restricts insulin's access to myocytes. The mechanism by which insulin crosses this continuous endothelium is critical to understand insulin action and insulin resistance; however, methodological obstacles have limited understanding of endothelial insulin transport in vivo. Here, we present an intravital microscopy technique to measure the rate of insulin efflux across the endothelium of SkM capillaries. This method involves development of a fully bioactive, fluorescent insulin probe, a gastrocnemius preparation for intravital microscopy, an automated vascular segmentation algorithm, and the use of mathematical models to estimate endothelial transport parameters. We combined direct visualization of insulin efflux from SkM capillaries with modeling of insulin efflux kinetics to identify fluid-phase transport as the major mode of transendothelial insulin efflux in mice. Model-independent experiments demonstrating that insulin movement is neither saturable nor affected by insulin receptor antagonism supported this result. Our finding that insulin enters the SkM interstitium by fluid-phase transport may have implications in the pathophysiology of SkM insulin resistance as well as in the treatment of diabetes with various insulin analogs.
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21 MeSH Terms