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Expression of Calgranulin Genes S100A8, S100A9 and S100A12 Is Modulated by n-3 PUFA during Inflammation in Adipose Tissue and Mononuclear Cells.
Shah RD, Xue C, Zhang H, Tuteja S, Li M, Reilly MP, Ferguson JF
(2017) PLoS One 12: e0169614
MeSH Terms: Adipose Tissue, Adult, Antioxidants, Buttocks, Calgranulin A, Calgranulin B, Case-Control Studies, Docosahexaenoic Acids, Eicosapentaenoic Acid, Endotoxemia, Female, Gene Expression Regulation, Healthy Volunteers, Humans, Lipopolysaccharides, Male, Monocytes, S100A12 Protein, Signal Transduction
Show Abstract · Added June 6, 2017
Calgranulin genes (S100A8, S100A9 and S100A12) play key immune response roles in inflammatory disorders, including cardiovascular disease. Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) may have systemic and adipose tissue-specific anti-inflammatory and cardio-protective action. Interactions between calgranulins and the unsaturated fatty acid arachidonic acid (AA) have been reported, yet little is known about the relationship between calgranulins and the LC n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We explored tissue-specific action of calgranulins in the setting of evoked endotoxemia and n-3 PUFA supplementation. Expression of calgranulins in adipose tissue in vivo was assessed by RNA sequencing (RNASeq) before and after n-3 PUFA supplementation and evoked endotoxemia in the fenofibrate and omega-3 fatty acid modulation of endotoxemia (FFAME) Study. Subjects received n-3 PUFA (n = 8; 3600mg/day EPA/DHA) or matched placebo (n = 6) for 6-8 weeks, before completing an endotoxin challenge (LPS 0.6 ng/kg). Calgranulin genes were up-regulated post-LPS, with greater increase in n-3 PUFA (S100A8 15-fold, p = 0.003; S100A9 7-fold, p = 0.003; S100A12 28-fold, p = 0.01) compared to placebo (S100A8 2-fold, p = 0.01; S100A9 1.4-fold, p = 0.4; S100A12 5-fold, p = 0.06). In an independent evoked endotoxemia study, calgranulin gene expression correlated with the systemic inflammatory response. Through in vivo and in vitro interrogation we highlight differential responses in adipocytes and mononuclear cells during inflammation, with n-3 PUFA leading to increased calgranulin expression in adipose, but decreased expression in circulating cells. In conclusion, we present a novel relationship between n-3 PUFA anti-inflammatory action in vivo and cell-specific modulation of calgranulin expression during innate immune activation.
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19 MeSH Terms
Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection.
Zackular JP, Moore JL, Jordan AT, Juttukonda LJ, Noto MJ, Nicholson MR, Crews JD, Semler MW, Zhang Y, Ware LB, Washington MK, Chazin WJ, Caprioli RM, Skaar EP
(2016) Nat Med 22: 1330-1334
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Anti-Bacterial Agents, Bacterial Proteins, Bacterial Toxins, Calgranulin B, Cecum, Child, Clostridium Infections, Clostridium difficile, Cohort Studies, Colon, Cytokines, Diet, Disease Models, Animal, Disease Susceptibility, Enterotoxins, Female, Gastrointestinal Microbiome, Humans, Male, Mass Spectrometry, Mice, Mice, Knockout, Middle Aged, Polymerase Chain Reaction, Prospective Studies, RNA, Ribosomal, 16S, Trace Elements, Young Adult, Zinc
Show Abstract · Added April 8, 2017
Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile-associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.
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33 MeSH Terms
Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection.
Clark HL, Jhingran A, Sun Y, Vareechon C, de Jesus Carrion S, Skaar EP, Chazin WJ, Calera JA, Hohl TM, Pearlman E
(2016) J Immunol 196: 336-44
MeSH Terms: Adolescent, Adult, Aged, Animals, Aspergillus fumigatus, Biological Transport, Calgranulin A, Calgranulin B, Chelating Agents, Cornea, Disease Models, Animal, Humans, Hyphae, Keratitis, Leukocyte L1 Antigen Complex, Manganese, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neutrophils, Phagocytosis, Pulmonary Aspergillosis, Spores, Fungal, Young Adult, Zinc
Show Abstract · Added February 5, 2016
Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9(-/-) mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9(-/-) mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus ∆zafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage-specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin.
Copyright © 2015 by The American Association of Immunologists, Inc.
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26 MeSH Terms
Myeloid-related protein-8/14 facilitates bacterial growth during pneumococcal pneumonia.
Achouiti A, Vogl T, Endeman H, Mortensen BL, Laterre PF, Wittebole X, van Zoelen MA, Zhang Y, Hoogerwerf JJ, Florquin S, Schultz MJ, Grutters JC, Biesma DH, Roth J, Skaar EP, van 't Veer C, de Vos AF, van der Poll T
(2014) Thorax 69: 1034-42
MeSH Terms: Animals, Bronchoalveolar Lavage Fluid, Calgranulin B, Disease Models, Animal, Female, Humans, Lung, Male, Mice, Mice, Inbred C57BL, Pneumonia, Pneumococcal, Streptococcus pneumoniae
Show Abstract · Added January 24, 2015
BACKGROUND - Streptococcus pneumoniae is the most commonly identified pathogen in community-acquired pneumonia (CAP). Myeloid-related protein (MRP) 8/14 is a major component of neutrophils that is released upon infection or injury. MRP8/14 is essential for protective immunity during infection by a variety of micro-organisms through its capacity to chelate manganese and zinc. Here, we aimed to determine the role of MRP8/14 in pneumococcal pneumonia.
METHODS - MRP8/14 was determined in bronchoalveolar lavage fluid (BALF) and serum of CAP patients, in lung tissue of patients who had succumbed to pneumococcal pneumonia, and in BALF of healthy subjects challenged with lipoteichoic acid (a component of the gram-positive bacterial cell wall) via the airways. Pneumonia was induced in MRP14 deficient and normal wildtype mice. The effect of MRP8/14 on S. pneumoniae growth was studied in vitro.
RESULTS - CAP patients displayed high MRP8/14 levels in BALF, lung tissue and serum. Healthy subjects challenged with lipoteichoic acid demonstrated elevated MRP8/14 in BALF. Likewise, mice with pneumococcal pneumonia had high MRP8/14 levels in lungs and the circulation. MRP14 deficiency, however, was associated with reduced bacterial growth and lethality, in the absence of notable effects on the inflammatory response. High zinc levels strongly inhibited growth of S. pneumoniae in vitro, which was partially reversed by MRP8/14.
CONCLUSIONS - In sharp contrast to its previously reported host-protective role in several infections, the present results reveal that in a model of CAP, MRP8/14 is misused by S. pneumoniae, facilitating bacterial growth by attenuating zinc toxicity toward the pathogen.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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12 MeSH Terms
Acinetobacter baumannii response to host-mediated zinc limitation requires the transcriptional regulator Zur.
Mortensen BL, Rathi S, Chazin WJ, Skaar EP
(2014) J Bacteriol 196: 2616-26
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Bacterial Proteins, Calgranulin B, Gene Expression Regulation, Bacterial, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Pneumonia, Bacterial, RNA, Bacterial, Regulatory Elements, Transcriptional, Zinc
Show Abstract · Added May 19, 2014
Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia in intensive care units, and the increasing rates of antibiotic resistance make treating these infections challenging. Consequently, there is an urgent need to develop new antimicrobials to treat A. baumannii infections. One potential therapeutic option is to target bacterial systems involved in maintaining appropriate metal homeostasis, processes that are critical for the growth of pathogens within the host. The A. baumannii inner membrane zinc transporter ZnuABC is required for growth under low-zinc conditions and for A. baumannii pathogenesis. The expression of znuABC is regulated by the transcriptional repressor Zur. To investigate the role of Zur during the A. baumannii response to zinc limitation, a zur deletion mutant was generated, and transcriptional changes were analyzed using RNA sequencing. A number of Zur-regulated genes were identified that exhibit increased expression both when zur is absent and under low-zinc conditions, and Zur binds to predicted Zur box sequences of several genes affected by zinc levels or the zur mutation. Furthermore, the zur mutant is impaired for growth in the presence of both high and low zinc levels compared to wild-type A. baumannii. Finally, the zur mutant exhibits a defect in dissemination in a mouse model of A. baumannii pneumonia, establishing zinc sensing as a critical process during A. baumannii infection. These results define Zur-regulated genes within A. baumannii and demonstrate a requirement for Zur in the A. baumannii response to the various zinc levels experienced within the vertebrate host.
Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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15 MeSH Terms
Imaging mass spectrometry for assessing temporal proteomics: analysis of calprotectin in Acinetobacter baumannii pulmonary infection.
Moore JL, Becker KW, Nicklay JJ, Boyd KL, Skaar EP, Caprioli RM
(2014) Proteomics 14: 820-828
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Calgranulin A, Calgranulin B, Humans, Immunity, Innate, Leukocyte L1 Antigen Complex, Lung, Mice, Molecular Imaging, Neutrophils, Proteomics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added March 7, 2014
Imaging MS is routinely used to show spatial localization of proteins within a tissue sample and can also be employed to study temporal protein dynamics. The antimicrobial S100 protein calprotectin, a heterodimer of subunits S100A8 and S100A9, is an abundant cytosolic component of neutrophils. Using imaging MS, calprotectin can be detected as a marker of the inflammatory response to bacterial challenge. In a murine model of Acinetobacter baumannii pneumonia, protein images of S100A8 and S100A9 collected at different time points throughout infection aid in visualization of the innate immune response to this pathogen. Calprotectin is detectable within 6 h of infection as immune cells respond to the invading pathogen. As the bacterial burden decreases, signals from the inflammatory proteins decrease. Calprotectin is no longer detectable 96-144 h post infection, correlating to a lack of detectable bacterial burden in lungs. These experiments provide a label-free, multiplexed approach to study host response to a bacterial threat and eventual clearance of the pathogen over time.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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14 MeSH Terms
Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens.
Damo SM, Kehl-Fie TE, Sugitani N, Holt ME, Rathi S, Murphy WJ, Zhang Y, Betz C, Hench L, Fritz G, Skaar EP, Chazin WJ
(2013) Proc Natl Acad Sci U S A 110: 3841-6
MeSH Terms: Amino Acid Substitution, Binding Sites, Calgranulin A, Calgranulin B, Crystallography, X-Ray, Histidine, Host-Pathogen Interactions, Humans, Immunity, Innate, Leukocyte L1 Antigen Complex, Manganese, Models, Molecular, Mutagenesis, Site-Directed, Protein Multimerization, Recombinant Proteins, Staphylococcus aureus, Zinc
Show Abstract · Added March 7, 2014
The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn(2+) and Zn(2+) with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn(2+) sequestration. The asymmetry of the CP heterodimer creates a single Mn(2+)-binding site from six histidine residues, which distinguishes CP from all other Mn(2+)-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn(2+) and Zn(2+) being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn(2+) sequestration. These data establish the importance of Mn(2+) sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.
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3 Members
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17 MeSH Terms
S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3.
Ghavami S, Eshragi M, Ande SR, Chazin WJ, Klonisch T, Halayko AJ, McNeill KD, Hashemi M, Kerkhoff C, Los M
(2010) Cell Res 20: 314-31
MeSH Terms: Adenine, Apoptosis, Autophagy, Autophagy-Related Protein 12, Autophagy-Related Protein 5, Calgranulin A, Calgranulin B, Cell Line, Humans, Lysosomes, Macrolides, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins, Reactive Oxygen Species, Small Ubiquitin-Related Modifier Proteins, Vacuolar Proton-Translocating ATPases
Show Abstract · Added March 12, 2014
The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity in various cells of different origins. Here, we present evidence that the underlying molecular mechanisms involve both programmed cell death I (PCD I, apoptosis) and PCD II (autophagy)-like death. Treatment of cells with S100A8/A9 caused the increase of Beclin-1 expression as well as Atg12-Atg5 formation. S100A8/A9-induced cell death was partially inhibited by the specific PI3-kinase class III inhibitor, 3-methyladenine (3-MA), and by the vacuole H(+)-ATPase inhibitor, bafilomycin-A1 (Baf-A1). S100A8/A9 provoked the translocation of BNIP3, a BH3 only pro-apoptotic Bcl2 family member, to mitochondria. Consistent with this finding, DeltaTM-BNIP3 overexpression partially inhibited S100A8/A9-induced cell death, decreased reactive oxygen species (ROS) generation, and partially protected against the decrease in mitochondrial transmembrane potential in S100A8/A9-treated cells. In addition, either DeltaTM-BNIP3 overexpression or N-acetyl-L-cysteine co-treatment decreased lysosomal activation in cells treated with S100A8/A9. Our data indicate that S100A8/A9-promoted cell death occurs through the cross-talk of mitochondria and lysosomes via ROS and the process involves BNIP3.
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19 MeSH Terms
S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis.
Ghavami S, Chitayat S, Hashemi M, Eshraghi M, Chazin WJ, Halayko AJ, Kerkhoff C
(2009) Eur J Pharmacol 625: 73-83
MeSH Terms: Animals, Apoptosis, Calgranulin A, Calgranulin B, Epithelial Cells, Gene Expression Regulation, Neoplastic, Humans, Immunotherapy, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms
Show Abstract · Added March 12, 2014
Correlations exist between the abundance of S100 proteins and disease pathologies. Indeed, this is evidenced by the heterodimeric S100 protein complex S100A8/A9 which has been shown to be involved in inflammatory and neoplastic disorders. However, S100A8/A9 appears as a Janus-faced molecule in this context. On the one hand, it is a powerful apoptotic agent produced by immune cells, making it a very fascinating tool in the battle against cancer. It spears the risk to induce auto-immune response and may serve as a lead compound for cancer-selective therapeutics. In contrast, S100A8/A9 expression in cancer cells has also been associated with tumor development, cancer invasion or metastasis. Clearly, there is a dichotomy and future investigations into the role of S100A8/A9 in cancer biology need to consider both sides of the same coin.
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11 MeSH Terms
S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway.
Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M
(2008) J Leukoc Biol 83: 1484-92
MeSH Terms: Calgranulin A, Calgranulin B, Cell Line, Tumor, Cell Proliferation, Extracellular Signal-Regulated MAP Kinases, Female, HMGB1 Protein, Humans, MAP Kinase Signaling System, NF-kappa B, Phosphorylation, Receptor for Advanced Glycation End Products, Receptors, Immunologic
Show Abstract · Added May 19, 2014
The complex formed by two members of the S100 calcium-binding protein family, S100A8/A9, exerts apoptosis-inducing activity against various cells, especially tumor cells. Here, we present evidence that S100A8/A9 also has cell growth-promoting activity at low concentrations. Receptor of advanced glycation end product (RAGE) gene silencing and cotreatment with a RAGE-specific blocking antibody revealed that this activity was mediated via RAGE ligation. To investigate the signaling pathways, MAPK phosphorylation and NF-kappaB activation were characterized in S100A8/A9-treated cells. S100A8/A9 caused a significant increase in p38 MAPK and p44/42 kinase phosphorylation, and the status of stress-activated protein kinase/JNK phosphorylation remained unchanged. Treatment of cells with S100A8/A9 also enhanced NF-kappaB activation. RAGE small interfering RNA pretreatment abrogated the S100A8/A9-induced NF-kappaB activation. Our data indicate that S100A8/A9-promoted cell growth occurs through RAGE signaling and activation of NF-kappaB.
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13 MeSH Terms