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IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.
Chopra S, Giovanelli P, Alvarado-Vazquez PA, Alonso S, Song M, Sandoval TA, Chae CS, Tan C, Fonseca MM, Gutierrez S, Jimenez L, Subbaramaiah K, Iwawaki T, Kingsley PJ, Marnett LJ, Kossenkov AV, Crespo MS, Dannenberg AJ, Glimcher LH, Romero-Sandoval EA, Cubillos-Ruiz JR
(2019) Science 365:
MeSH Terms: Animals, Cells, Cultured, Cyclooxygenase 2, Dinoprostone, Endoribonucleases, Humans, Leukocytes, Mice, Mice, Inbred C57BL, Myeloid Cells, Pain, Postoperative, Promoter Regions, Genetic, Prostaglandin-E Synthases, Protein-Serine-Threonine Kinases, Signal Transduction, Unfolded Protein Response, Visceral Pain, X-Box Binding Protein 1
Show Abstract · Added March 12, 2020
Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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18 MeSH Terms
Regulation of leukocyte function by citric acid cycle intermediates.
Patil NK, Bohannon JK, Hernandez A, Patil TK, Sherwood ER
(2019) J Leukoc Biol 106: 105-117
MeSH Terms: Animals, Citric Acid, Citric Acid Cycle, Fumarates, Humans, Leukocytes, Reactive Oxygen Species, Succinates, Succinic Acid
Show Abstract · Added March 18, 2020
Cellular metabolism is a means of generating ATP to provide energy for key cellular functions. However, recent research shows that citric acid cycle intermediates target vital cellular functions of the innate immune system. Succinate, itaconate, citrate, and fumarate have been shown to mediate or regulate important myeloid cell functions during infection and inflammation. This review covers the regulatory functions of citric acid cycle intermediates in myeloid cells and discusses potential translational applications, key mechanistic questions, and future research directions.
©2019 Society for Leukocyte Biology.
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9 MeSH Terms
iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.
Park HJ, Lee SW, Im W, Kim M, Van Kaer L, Hong S
(2019) Mediators Inflamm 2019: 3540974
MeSH Terms: Animals, Brain, Cytokines, Disease Models, Animal, Disease Progression, Galactosylceramides, Genotype, Huntington Disease, Leukocytes, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 26, 2019
Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
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13 MeSH Terms
Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions.
Rigg RA, Healy LD, Chu TT, Ngo ATP, Mitrugno A, Zilberman-Rudenko J, Aslan JE, Hinds MT, Vecchiarelli LD, Morgan TK, Gruber A, Temple KJ, Lindsley CW, Duvernay MT, Hamm HE, McCarty OJT
(2019) Platelets 30: 126-135
MeSH Terms: Animals, Biomarkers, Blood Platelets, Cell Communication, Cytoplasmic Granules, Flow Cytometry, Humans, Leukocytes, Male, Papio, Platelet Activation, Platelet Aggregation, Receptors, Thrombin
Show Abstract · Added March 24, 2020
Human platelets express two protease-activated receptors (PARs), PAR1 (F2R) and PAR4 (F2RL3), which are activated by a number of serine proteases that are generated during pathological events and cause platelet activation. Recent interest has focused on PAR4 as a therapeutic target, given PAR4 seems to promote experimental thrombosis and procoagulant microparticle formation, without a broadly apparent role in hemostasis. However, it is not yet known whether PAR4 activity plays a role in platelet-leukocyte interactions, which are thought to contribute to both thrombosis and acute or chronic thrombo-inflammatory processes. We sought to determine whether PAR4 activity contributes to granule secretion from activated platelets and platelet-leukocyte interactions. We performed in vitro and ex vivo studies of platelet granule release and platelet-leukocyte interactions in the presence of PAR4 agonists including PAR4 activating peptide, thrombin, cathepsin G, and plasmin in combination with small-molecule PAR4 antagonists. Activation of human platelets with thrombin, cathepsin G, or plasmin potentiated platelet dense granule secretion that was specifically impaired by PAR4 inhibitors. Platelet-leukocyte interactions and platelet P-selectin exposure the following stimulation with PAR4 agonists were also impaired by activated PAR4 inhibition in either a purified system or in whole blood. These results indicate PAR4-specific promotion of platelet granule release and platelet-leukocyte aggregate formation and suggest that pharmacological control of PAR4 activity could potentially attenuate platelet granule release or platelet-leukocyte interaction-mediated pathological processes.
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MeSH Terms
Omega-3 polyunsaturated fatty acids attenuate inflammatory activation and alter differentiation in human adipocytes.
Ferguson JF, Roberts-Lee K, Borcea C, Smith HM, Midgette Y, Shah R
(2019) J Nutr Biochem 64: 45-49
MeSH Terms: Adipocytes, Cell Differentiation, Cells, Cultured, Coculture Techniques, Docosahexaenoic Acids, Eicosapentaenoic Acid, Fatty Acids, Omega-3, Humans, Inflammation, Leukocytes, Lipid Droplets, Lipopolysaccharides, Macrophages, Obesity
Show Abstract · Added April 2, 2019
BACKGROUND - Omega-3 polyunsaturated fatty acids, specifically the fish-oil-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been proposed as inflammation-resolving agents via their effects on adipose tissue.
OBJECTIVE - We proposed to determine the effects of EPA and DHA on human adipocyte differentiation and inflammatory activation in vitro.
METHODS - Primary human subcutaneous adipocytes from lean and obese subjects were treated with 100 μM EPA and/or DHA throughout differentiation (differentiation studies) or for 72 h postdifferentiation (inflammatory studies). THP-1 monocytes were added to adipocyte wells for co-culture experiments. Subcutaneous and visceral adipose explants from obese subjects were treated for 72 h with EPA and DHA. Oil Red O staining was performed on live cells. Cells were collected for mRNA analysis by quantitative polymerase chain reaction, and media were collected for protein quantification by enzyme-linked immunosorbent assay.
RESULTS - Incubation with EPA and/or DHA attenuated inflammatory response to lipopolysaccharide (LPS) and monocyte co-culture with reduction in post-LPS mRNA expression and protein levels of IL6, CCL2 and CX3CL1. Expression of inflammatory genes was also reduced in the endogenous inflammatory response in obese adipose. Both DHA and EPA reduced lipid droplet formation and lipogenic gene expression without alteration in expression of adipogenic genes or adiponectin secretion.
CONCLUSIONS - EPA and DHA attenuate inflammatory activation of in vitro human adipocytes and reduce lipogenesis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Substrate stiffness heterogeneities disrupt endothelial barrier integrity in a micropillar model of heterogeneous vascular stiffening.
VanderBurgh JA, Hotchkiss H, Potharazu A, Taufalele PV, Reinhart-King CA
(2018) Integr Biol (Camb) 10: 734-746
MeSH Terms: Adherens Junctions, Animals, Aorta, Atherosclerosis, Cattle, Cell Adhesion, Cell Communication, Cell Movement, Dimethylpolysiloxanes, Endothelial Cells, Endothelium, Vascular, Focal Adhesions, Human Umbilical Vein Endothelial Cells, Humans, Leukocytes, Materials Testing, Neutrophils, Phenotype, Tunica Intima, Vascular Stiffness, Vinculin
Show Abstract · Added April 10, 2019
Intimal stiffening has been linked with increased vascular permeability and leukocyte transmigration, hallmarks of atherosclerosis. However, recent evidence indicates age-related intimal stiffening is not uniform but rather characterized by increased point-to-point heterogeneity in subendothelial matrix stiffness, the impact of which is much less understood. To investigate the impact of spatially heterogeneous matrix rigidity on endothelial monolayer integrity, we develop a micropillar model to introduce closely-spaced, step-changes in substrate rigidity and compare endothelial monolayer phenotype to rigidity-matched, uniformly stiff and compliant substrates. We found equivalent disruption of adherens junctions within monolayers on step-rigidity and uniformly stiff substrates relative to uniformly compliant substrates. Similarly, monolayers cultured on step-rigidity substrates exhibited equivalent percentages of leukocyte transmigration to monolayers on rigidity-matched, uniformly stiff substrates. Adherens junction tension and focal adhesion density, but not size, increased within monolayers on step-rigidity and uniformly stiff substrates compared to more compliant substrates suggesting that elevated tension is disrupting adherens junction integrity. Leukocyte transmigration frequency and time, focal adhesion size, and focal adhesion density did not differ between stiff and compliant sub-regions of step-rigidity substrates. Overall, our results suggest that endothelial monolayers exposed to mechanically heterogeneous substrates adopt the phenotype associated with the stiffer matrix, indicating that spatial heterogeneities in intimal stiffness observed with age could disrupt endothelial barrier integrity and contribute to atherogenesis.
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21 MeSH Terms
LCP1 preferentially binds clasped αMβ2 integrin and attenuates leukocyte adhesion under flow.
Tseng HY, Samarelli AV, Kammerer P, Scholze S, Ziegler T, Immler R, Zent R, Sperandio M, Sanders CR, Fässler R, Böttcher RT
(2018) J Cell Sci 131:
MeSH Terms: Animals, Cell Adhesion, Cell Membrane, Cytoplasm, HEK293 Cells, Humans, Leukocytes, Macrophage-1 Antigen, Mice, Mice, Inbred C57BL, Microfilament Proteins, Protein Binding, Protein Conformation, RAW 264.7 Cells
Show Abstract · Added November 21, 2018
Integrins are α/β heterodimers that interconvert between inactive and active states. In the active state the α/β cytoplasmic domains recruit integrin-activating proteins and separate the transmembrane and cytoplasmic (TMcyto) domains (unclasped TMcyto). Conversely, in the inactive state the α/β TMcyto domains bind integrin-inactivating proteins, resulting in the association of the TMcyto domains (clasped TMcyto). Here, we report the isolation of integrin cytoplasmic tail interactors using either lipid bicelle-incorporated integrin TMcyto domains (α5, αM, αIIb, β1, β2 and β3 integrin TMcyto) or a clasped, lipid bicelle-incorporated αMβ2 TMcyto. Among the proteins found to preferentially bind clasped rather than the isolated αM and β2 subunits was L-plastin (LCP1, also known as plastin-2), which binds to and maintains the inactive state of αMβ2 integrin and thereby regulates leukocyte adhesion to integrin ligands under flow. Our findings offer a global view on cytoplasmic proteins interacting with different integrins and provide evidence for the existence of conformation-specific integrin interactors.
© 2018. Published by The Company of Biologists Ltd.
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14 MeSH Terms
Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.
Kallianpur AR, Gerschenson M, Hulgan T, Kaur H, Clifford DB, Haas DW, Murdock DG, McArthur JC, Samuels DC, Simpson DM
(2018) AIDS Res Hum Retroviruses 34: 942-949
MeSH Terms: Adult, Alleles, Anti-HIV Agents, CD4 Lymphocyte Count, Case-Control Studies, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genotype, HIV Infections, HIV-1, Hemochromatosis Protein, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Mitochondria, RNA, Viral
Show Abstract · Added December 11, 2019
Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.
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Isolating the influences of fluid dynamics on selectin-mediated particle rolling at venular junctional regions.
Jung JJ, Grayson KA, King MR, Lamkin-Kennard KA
(2018) Microvasc Res 118: 144-154
MeSH Terms: Animals, Cell Adhesion, Humans, Hydrodynamics, Inflammation, Leukocyte Rolling, Leukocytes, Lewis X Antigen, Microspheres, Models, Cardiovascular, P-Selectin, Sialyl Lewis X Antigen, Signal Transduction, Venules
Show Abstract · Added April 15, 2019
The objective of this study was to isolate the impact of hydrodynamics on selectin-mediated cell rolling in branched microvessels. Significant advancements have been made in furthering the understanding of complex interactions between biochemical and physical factors in the inflammatory cascade in simplified planar geometries. However, few studies have sought to quantify the effects of branched configurations and to isolate the effects of associated fluid forces. Experimental techniques were developed to perform in vitro adhesion experiments in Y-shaped micro-slides. The micro-slides were coated with P-selectin and microspheres coated with Sialyl-Lewis were observed as they rolled in the chambers at different wall shear stresses. Study results revealed that microsphere rolling velocities and rolling flux were lowest in regions closest to the apex of a junctional region and were dependent on both branch angle and wall shear stress. The regions closest to the junctional region were shown to have low bulk flow velocities and shear stresses using computational fluid dynamics (CFD) modeling. Collectively, the study demonstrates that despite the presence of a uniform coating of P-selectin, hydrodynamic factors associated with the chamber geometry yield non-uniform effects on particle behavior. These findings could explain why cells have been observed to preferentially adhere or transmigrate near junctional regions. Future characterization of inflammatory processes in microvascular network configurations is therefore crucial for furthering our fundamental understanding of inflammation.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms
Protective Role of mPGES-1 (Microsomal Prostaglandin E Synthase-1)-Derived PGE (Prostaglandin E) and the Endothelial EP4 (Prostaglandin E Receptor) in Vascular Responses to Injury.
Hao H, Hu S, Wan Q, Xu C, Chen H, Zhu L, Xu Z, Meng J, Breyer RM, Li N, Liu DP, FitzGerald GA, Wang M
(2018) Arterioscler Thromb Vasc Biol 38: 1115-1124
MeSH Terms: Animals, Cell Adhesion, Cell Proliferation, Cells, Cultured, Dinoprostone, Disease Models, Animal, Endothelial Cells, Female, Femoral Artery, Humans, Leukocytes, Male, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Neointima, Prostaglandin-E Synthases, Re-Epithelialization, Receptors, Epoprostenol, Receptors, Prostaglandin E, EP4 Subtype, Signal Transduction, Vascular System Injuries
Show Abstract · Added May 29, 2018
OBJECTIVE - Deletion of mPGES-1 (microsomal prostaglandin E synthase-1)-an anti-inflammatory target alternative to COX (cyclooxygenase)-2-attenuates injury-induced neointima formation in mice. This is attributable to the augmented levels of PGI (prostacyclin)-a known restraint of the vascular response to injury, acting via IP (I prostanoid receptor). To examine the role of mPGES-1-derived PGE (prostaglandin E) in vascular remodeling without the IP.
APPROACH AND RESULTS - Mice deficient in both IP and mPGES-1 (DKO [double knockout] and littermate controls [IP KO (knockout)]) were subjected to angioplasty wire injury. Compared with the deletion of IP alone, coincident deletion of IP and mPGES-1 increased neointima formation, without affecting media area. Early pathological changes include impaired reendothelialization and increased leukocyte invasion in neointima. Endothelial cells (ECs), but not vascular smooth muscle cells, isolated from DKOs exhibited impaired cell proliferation. Activation of EP (E prostanoid receptor) 4 (and EP2, to a lesser extent), but not of EP1 or EP3, promoted EC proliferation. EP4 antagonism inhibited proliferation of mPGES-1-competent ECs, but not of mPGES-1-deficient ECs, which showed suppressed PGE production. EP4 activation inhibited leukocyte adhesion to ECs in vitro, promoted reendothelialization, and limited neointima formation post-injury in the mouse. Endothelium-restricted deletion of EP4 in mice suppressed reendothelialization, increased neointimal leukocytes, and exacerbated neointimal formation.
CONCLUSIONS - Removal of the IP receptors unmasks a protective role of mPGES-1-derived PGE in limiting injury-induced vascular hyperplasia. EP4, in the endothelial compartment, is essential to promote reendothelialization and restrain neointimal formation after injury. Activating EP4 bears therapeutic potential to prevent restenosis after percutaneous coronary intervention.
© 2018 American Heart Association, Inc.
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22 MeSH Terms