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Cell-free hemoglobin augments acute kidney injury during experimental sepsis.
Shaver CM, Paul MG, Putz ND, Landstreet SR, Kuck JL, Scarfe L, Skrypnyk N, Yang H, Harrison FE, de Caestecker MP, Bastarache JA, Ware LB
(2019) Am J Physiol Renal Physiol 317: F922-F929
MeSH Terms: Acute Kidney Injury, Animals, Cell Line, Cell Survival, Cell-Free System, Cytokines, Female, Glomerular Filtration Rate, Hemoglobins, Hepatitis A Virus Cellular Receptor 1, Kidney Tubules, Lipocalin-2, Male, Mice, Mice, Inbred C57BL, Sepsis, Survival Analysis
Show Abstract · Added May 10, 2020
Acute kidney injury is a common complication of severe sepsis and contributes to high mortality. The molecular mechanisms of acute kidney injury during sepsis are not fully understood. Because hemoproteins, including myoglobin and hemoglobin, are known to mediate kidney injury during rhabdomyolysis, we hypothesized that cell-free hemoglobin (CFH) would exacerbate acute kidney injury during sepsis. Sepsis was induced in mice by intraperitoneal injection of cecal slurry (CS). To mimic elevated levels of CFH observed during human sepsis, mice also received a retroorbital injection of CFH or dextrose control. Four groups of mice were analyzed: sham treated (sham), CFH alone, CS alone, and CS + CFH. The addition of CFH to CS reduced 48-h survival compared with CS alone (67% vs. 97%, = 0.001) and increased the severity of illness. After 24 and 48 h, CS + CFH mice had a reduced glomerular filtration rate from baseline, whereas sham, CFH, and CS mice maintained baseline glomerular filtration rate. Biomarkers of acute kidney injury, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), were markedly elevated in CS+CFH compared with CS (8-fold for NGAL and 2.4-fold for KIM-1, < 0.002 for each) after 48 h. Histological examination showed a trend toward increased tubular injury in CS + CFH-exposed kidneys compared with CS-exposed kidneys. However, there were similar levels of renal oxidative injury and apoptosis in the CS + CFH group compared with the CS group. Kidney levels of multiple proinflammatory cytokines were similar between CS and CS + CFH groups. Human renal tubule cells (HK-2) exposed to CFH demonstrated increased cytotoxicity. Together, these results show that CFH exacerbates acute kidney injury in a mouse model of experimental sepsis, potentially through increased renal tubular injury.
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MeSH Terms
Resolution of Gastric Cancer-Promoting Inflammation: A Novel Strategy for Anti-cancer Therapy.
Piazuelo MB, Riechelmann RP, Wilson KT, Algood HMS
(2019) Curr Top Microbiol Immunol 421: 319-359
MeSH Terms: Cytokines, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Inflammation, Stomach Neoplasms, Tumor Microenvironment
Show Abstract · Added June 6, 2019
The connection between inflammation and cancer was initially recognized by Rudolf Virchow in the nineteenth century. During the last decades, a large body of evidence has provided support to his hypothesis, and now inflammation is recognized as one of the hallmarks of cancer, both in etiopathogenesis and ongoing tumor growth. Infection with the pathogen Helicobacter pylori is the primary causal factor in 90% of gastric cancer (GC) cases. As we increase our understanding of how chronic inflammation develops in the stomach and contributes to carcinogenesis, there is increasing interest in targeting cancer-promoting inflammation as a strategy to treat GC. Moreover, once cancer develops and anti-cancer immune responses are suppressed, there is evidence of a substantial shift in the microenvironment and new targets for immune therapy emerge. In this chapter, we provide insight into inflammation-related factors, including T lymphocytes, macrophages, pro-inflammatory chemokines, and cytokines, which promote H. pylori-associated GC initiation and growth. While intervening with chronic inflammation is not a new practice in rheumatology or gastroenterology, this approach has not been fully explored for its potential to prevent carcinogenesis or to contribute to the treatment of GC. This review highlights current and possible strategies for therapeutic intervention including (i) targeting pro-inflammatory mediators, (ii) targeting growth factors and pathways involved in angiogenesis in the gastric tumor microenvironment, and (iii) enhancing anti-tumor immunity. In addition, we highlight a significant number of clinical trials and discuss the importance of individual tumor characterization toward offering personalized immune-related therapy.
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8 MeSH Terms
Picturing Polarized Myeloid Phagocytes and Regulatory Cells by Mass Cytometry.
Roussel M, Bartkowiak T, Irish JM
(2019) Methods Mol Biol 1989: 217-226
MeSH Terms: Cytokines, Dendritic Cells, Flow Cytometry, Humans, Mass Spectrometry, Monocytes, Myeloid-Derived Suppressor Cells, Phagocytes, Phenotype, Single-Cell Analysis
Show Abstract · Added May 13, 2019
The immune monocyte/phagocyte system (MPS) includes numerous cell subsets of the myeloid lineage including monocyte, macrophage, and dendritic cell (DC) populations that are heterogeneous both phenotypically and functionally. Previously, we characterized these diverse MPS phenotypes with multi-parametric mass cytometry (CyTOF). In order to expansively characterize monocytes, macrophages, and dendritic cells, a CyTOF panel was designed to measure 35 identity-, activation-, and polarization-markers. Here we provide a protocol to define a reference map for the myeloid compartment, including sample preparation, to produce reference cell subsets from the monocyte/phagocyte system. In particular, we focused on monocyte-derived macrophages that were further polarized in vitro with cytokine stimulation (i.e., M-CSF, GM-CSF, IL-4, IL-10, IFNγ, and LPS), as well as monocyte-derived DCs, and myeloid-derived suppressor cells (MDSCs), generated in vitro from human bone marrow and/or peripheral blood.
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10 MeSH Terms
Hypoxia-inducible factors in CD4 T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity.
Cho SH, Raybuck AL, Blagih J, Kemboi E, Haase VH, Jones RG, Boothby MR
(2019) Proc Natl Acad Sci U S A 116: 8975-8984
MeSH Terms: Animals, Antibody Formation, B-Lymphocytes, Basic Helix-Loop-Helix Transcription Factors, CD4-Positive T-Lymphocytes, Cell Hypoxia, Cytokines, Germinal Center, Humans, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Immunity, Humoral, Immunization, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Transgenic, Receptors, CXCR5, Sheep, T-Lymphocytes, Helper-Inducer
Show Abstract · Added April 23, 2019
T cell help in humoral immunity includes interactions of B cells with activated extrafollicular CD4 and follicular T helper (Tfh) cells. Each can promote antibody responses but Tfh cells play critical roles during germinal center (GC) reactions. After restimulation of their antigen receptor (TCR) by B cells, helper T cells act on B cells via CD40 ligand and secreted cytokines that guide Ig class switching. Hypoxia is a normal feature of GC, raising questions about molecular mechanisms governing the relationship between hypoxia response mechanisms and T cell help to antibody responses. Hypoxia-inducible factors (HIF) are prominent among mechanisms that mediate cellular responses to limited oxygen but also are induced by lymphocyte activation. We now show that loss of HIF-1α or of both HIF-1α and HIF-2α in CD4 T cells compromised essential functions in help during antibody responses. HIF-1α depletion from CD4 T cells reduced frequencies of antigen-specific GC B cells, Tfh cells, and overall antigen-specific Ab after immunization with sheep red blood cells. Compound deficiency of HIF-1α and HIF-2α led to humoral defects after hapten-carrier immunization. Further, HIF promoted CD40L expression while restraining the FoxP3-positive CD4 cells in the CXCR5 follicular regulatory population. Glycolysis increases T helper cytokine expression, and HIF promoted glycolysis in T helper cells via TCR or cytokine stimulation, as well as their production of cytokines that direct antibody class switching. Indeed, IFN-γ elaboration by HIF-deficient in vivo-generated Tfh cells was impaired. Collectively, the results indicate that HIF transcription factors are vital components of the mechanisms of help during humoral responses.
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20 MeSH Terms
The Innate Immune Protein S100A9 Protects from T-Helper Cell Type 2-mediated Allergic Airway Inflammation.
Palmer LD, Maloney KN, Boyd KL, Goleniewska AK, Toki S, Maxwell CN, Chazin WJ, Peebles RS, Newcomb DC, Skaar EP
(2019) Am J Respir Cell Mol Biol 61: 459-468
MeSH Terms: Adaptive Immunity, Allergens, Alternaria, Alveolitis, Extrinsic Allergic, Animals, Bronchial Hyperreactivity, Bronchoalveolar Lavage Fluid, Calgranulin A, Calgranulin B, Cytokines, Forkhead Transcription Factors, Immunoglobulin E, Inflammation, Leukocyte L1 Antigen Complex, Lung, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Eosinophilia, Specific Pathogen-Free Organisms, T-Lymphocytes, Regulatory, Th2 Cells
Show Abstract · Added April 7, 2019
Calprotectin is a heterodimer of the proteins S100A8 and S100A9, and it is an abundant innate immune protein associated with inflammation. In humans, calprotectin transcription and protein abundance are associated with asthma and disease severity. However, mechanistic studies in experimental asthma models have been inconclusive, identifying both protective and pathogenic effects of calprotectin. To clarify the role of calprotectin in asthma, calprotectin-deficient and wild-type (WT) C57BL/6 mice were compared in a murine model of allergic airway inflammation. Mice were intranasally challenged with extracts of the clinically relevant allergen, (Alt Ext), or PBS every third day over 9 days. On Day 10, BAL fluid and lung tissue homogenates were harvested and allergic airway inflammation was assessed. Alt Ext challenge induced release of S100A8/S100A9 to the alveolar space and increased protein expression in the alveolar epithelium of WT mice. Compared with WT mice, mice displayed significantly enhanced allergic airway inflammation, including production of IL-13, CCL11, CCL24, serum IgE, eosinophil recruitment, and airway resistance and elastance. In response to Alt Ext, mice accumulated significantly more IL-13IL-5CD4 T-helper type 2 cells. mice also accumulated a significantly lower proportion of CD4 T regulatory (Treg) cells in the lung that had significantly lower expression of CD25. Calprotectin enhanced WT Treg cell suppressive activity . Therefore, this study identifies a role for the innate immune protein, S100A9, in protection from CD4 T-helper type 2 cell hyperinflammation in response to Alt Ext. This protection is mediated, at least in part, by CD4 Treg cell function.
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23 MeSH Terms
Genome-Wide Association and Functional Studies Reveal Novel Pharmacological Mechanisms for Allopurinol.
Brackman DJ, Yee SW, Enogieru OJ, Shaffer C, Ranatunga D, Denny JC, Wei WQ, Kamatani Y, Kubo M, Roden DM, Jorgenson E, Giacomini KM
(2019) Clin Pharmacol Ther 106: 623-631
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2, Aged, Aged, 80 and over, Allopurinol, Cytokines, Ethnic Groups, Female, Genome-Wide Association Study, Glucose Transport Proteins, Facilitative, Humans, Male, Middle Aged, Neoplasm Proteins, Oxypurinol, Prognosis, Uric Acid
Show Abstract · Added March 24, 2020
Allopurinol, which lowers uric acid (UA) concentration, is increasingly being recognized for its benefits in cardiovascular and renal disease. However, response to allopurinol is variable. We gathered samples from 4,446 multiethnic subjects for a genome-wide association study of allopurinol response. Consistent with previous studies, we observed that the Q141K variant in ABCG2 (rs2231142), which encodes the efflux pump breast cancer resistance protein (BCRP), associated with worse response to allopurinol. However, for the first time this association reached genome-wide level significance (P = 8.06 × 10 ). Additionally, we identified a novel association with a variant in GREM2 (rs1934341, P = 3.22 × 10 ). In vitro studies identified oxypurinol, the active metabolite of allopurinol, as an inhibitor of the UA transporter GLUT9, suggesting that oxypurinol may modulate UA reabsorption. These results provide strong evidence for a role of BCRP Q141K in allopurinol response, and suggest that allopurinol may have additional hypouricemic effects beyond xanthine oxidase inhibition.
© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.
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16 MeSH Terms
NDR Kinase Sid2 Drives Anillin-like Mid1 from the Membrane to Promote Cytokinesis and Medial Division Site Placement.
Willet AH, DeWitt AK, Beckley JR, Clifford DM, Gould KL
(2019) Curr Biol 29: 1055-1063.e2
MeSH Terms: Actin Cytoskeleton, Cell Cycle Checkpoints, Cytokinesis, Mitosis, Phosphorylation, Protein Kinases, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Signal Transduction
Show Abstract · Added April 10, 2019
In animals and fungi, cytokinesis is facilitated by the constriction of an actomyosin contractile ring (CR) [1]. In Schizosaccharomyces pombe, the CR forms mid-cell during mitosis from clusters of proteins at the medial cell cortex called nodes [2]. The anillin-like protein Mid1 localizes to nodes and is required for CR assembly at mid-cell [3]. When CR constriction begins, Mid1 leaves the division site. How Mid1 disassociates and whether this step is important for cytokinetic progression has been unknown. The septation initiation network (SIN), analogous to the Hippo pathway of multicellular organisms, is a signaling cascade that triggers node dispersal, CR assembly and constriction, and septum formation [4, 5]. We report that the terminal SIN kinase, Sid2 [6], phosphorylates Mid1 to drive its removal from the cortex at CR constriction onset. A Mid1 mutant that cannot be phosphorylated by Sid2 remains cortical during cytokinesis, over-accumulates in interphase nodes following cell division in a manner dependent on the SAD kinase Cdr2, advances the G2/M transition, precociously recruits other CR components to nodes, pulls Cdr2 aberrantly into the CR, and reduces rates of CR maturation and constriction. When combined with cdr2 mutants that affect node assembly or disassembly, gross defects in division site positioning result. Our findings identify Mid1 as a key Sid2 substrate for SIN-mediated remodeling of the division site for efficient cytokinesis and provide evidence that nodes serve to integrate signals coordinating cell cycle progression and cytokinesis.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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9 MeSH Terms
The F-BAR Domain of Rga7 Relies on a Cooperative Mechanism of Membrane Binding with a Partner Protein during Fission Yeast Cytokinesis.
Liu Y, McDonald NA, Naegele SM, Gould KL, Wu JQ
(2019) Cell Rep 26: 2540-2548.e4
MeSH Terms: Animals, COS Cells, Cell Cycle Proteins, Cell Membrane, Chlorocebus aethiops, Cytokinesis, GTPase-Activating Proteins, Microscopy, Confocal, Protein Domains, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Transfection
Show Abstract · Added April 10, 2019
F-BAR proteins bind the plasma membrane (PM) to scaffold and organize the actin cytoskeleton. To understand how F-BAR proteins achieve their PM association, we studied the localization of a Schizosaccharomyces pombe F-BAR protein Rga7, which requires the coiled-coil protein Rng10 for targeting to the division site during cytokinesis. We find that the Rga7 F-BAR domain directly binds a motif in Rng10 simultaneously with the PM, and that an adjacent Rng10 motif independently binds the PM. Together, these multivalent interactions significantly enhance Rga7 F-BAR avidity for membranes at physiological protein concentrations, ensuring the division site localization of Rga7. Moreover, the requirement for the F-BAR domain in Rga7 localization and function in cytokinesis is bypassed by tethering an Rga7 construct lacking its F-BAR to Rng10, indicating that at least some F-BAR domains are necessary but not sufficient for PM targeting and are stably localized to specific cortical positions through adaptor proteins.
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Myosin IIA drives membrane bleb retraction.
Taneja N, Burnette DT
(2019) Mol Biol Cell 30: 1051-1059
MeSH Terms: Actins, Animals, Blister, COS Cells, Cell Membrane, Cell Membrane Structures, Cell Movement, Cell Surface Extensions, Chlorocebus aethiops, Cytokinesis, Cytoplasm, Cytoskeletal Proteins, HeLa Cells, Humans, Myosin Type II, Nerve Tissue Proteins, Nonmuscle Myosin Type IIA, Nonmuscle Myosin Type IIB
Show Abstract · Added March 27, 2019
Membrane blebs are specialized cellular protrusions that play diverse roles in processes such as cell division and cell migration. Blebbing can be divided into three distinct phases: bleb nucleation, bleb growth, and bleb retraction. Following nucleation and bleb growth, the actin cortex, comprising actin, cross-linking proteins, and nonmuscle myosin II (MII), begins to reassemble on the membrane. MII then drives the final phase, bleb retraction, which results in reintegration of the bleb into the cellular cortex. There are three MII paralogues with distinct biophysical properties expressed in mammalian cells: MIIA, MIIB, and MIIC. Here we show that MIIA specifically drives bleb retraction during cytokinesis. The motor domain and regulation of the nonhelical tailpiece of MIIA both contribute to its ability to drive bleb retraction. These experiments have also revealed a relationship between faster turnover of MIIA at the cortex and its ability to drive bleb retraction.
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18 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