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Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages.

ABSTRACT: Trauma/hemorrhagic shock is associated with morbidity and mortality due to dysregulated inflammation, which is driven in part by monocytes/macrophages stimulated by injury-induced release of damage-associated molecular pattern (DAMP) molecules. MRP8/MRP14 is an endogenous DAMP involved in various inflammatory diseases, though its mechanism of action is unclear. Circulating MRP8/MRP14 levels in human blunt trauma nonsurvivors were significantly lower than those of survivors (P < 0.001). Human monocytic THP-1 cells stimulated with MRP8/MRP14 expressed the chemokine IFN-? inducible protein 10 (IP-10)/CXCL10. Circulating IP-10 levels in human blunt trauma patients were correlated positively with MRP8/MRP14 levels (r = 0.396, P < 0.001), and were significantly lower in trauma nonsurvivors than in survivors (P < 0.001). We therefore sought to determine the mechanisms by which MRP8/MRP14 stimulates IP-10 in monocytes/macrophages, and found that induction of IP-10 by MRP8/MRP14 required Toll-like receptor 4 and TRIF but not MyD88. Full induction of IP-10 by MRP8/MRP14 required synergy between the transcription factors NF-?B and IFN regulatory factor 3 (IRF3). The receptor for IP-10 is CXCR3, and MRP8/MRP14-induced chemotaxis of CXCR3(+) cells was dependent on the production of IP-10 in monocytes/macrophages. Furthermore, in vivo study with a mouse trauma/hemorrhagic shock model showed that administration of neutralizing antibody against MRP8 prevented activation of NF-?B and IRF3 as well as IP-10 production. Thus, the current study identified a novel signaling mechanism that controls IP-10 expression in monocytes/macrophages by MRP8/MRP14, which may play an important role in injury-induced inflammation.

PROVIDER: S-EPMC4285539 | BioStudies | 2015-01-01T00:00:00Z

REPOSITORIES: biostudies

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MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance.

Project description:OBJECTIVE:Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance. SUBJECTS AND RESULTS:Wild-type (WT) and Mrp14-/- mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14-/- mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14-/- macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14-/- macrophages. CONCLUSION:Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.

| S-EPMC6821582 | BioStudies

Project description:Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14(-/-)) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14(-/-) macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14(-/-) neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia.

| S-EPMC3486918 | BioStudies

Genome-wide expression analysis demonstrates a dominant role of TLR4 for activation of human phagocytes by the alarmin MRP8

Project description:The alarmins myeloid-related protein (MRP) 8 and MRP14 are the dominant cytoplasmic proteins in phagocytes. After release by activated phagocytes extracellular MRP8/MRP14 complexes promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis or inflammatory bowel disease. As receptors for the pro-inflammatory effects of human MRP8, the active component of the MRP8/MRP14-complex, Toll-like receptor (TLR) 4 and the multi-ligand receptor of advanced glycation end products (RAGE) are controversial discussed. Using a comparative bioinformatics analysis between genome-wide response patterns of monocytes to MRP8, endotoxin and different cytokines we demonstrated a dominant role of TLR4 during MRP8-mediated phagocyte activation. The relevance of this signaling pathway could be confirmed in independent cell models for TLR4 and RAGE dependent signaling in mouse and man. In addition to well-known proinflammatory functions of MRP8 our systems biology approach unraveled a novel anti-apoptotic effect of MRP8 on monocytes which was confirmed in independent functional experiments. Our data define the dominance of the TLR4-MRP8 axis in activation of human phagocytes which represents a novel attractive target for modulation of overwhelming innate immune responses. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Human blood monocyte stimulated with various stimuli (control, MRP8, LPS, TNF, IL1) were selected for RNA extraction and hybridization on Affymetrix microarrays.

| E-GEOD-56681 | BioStudies

Increase of calcium levels in epithelial cells induces translocation of calcium-binding proteins migration inhibitory factor-related protein 8 (MRP8) and MRP14 to keratin intermediate filaments.

Project description:Migration inhibitory factor-related protein 8 (MRP8) and MRP14, two S-100-like Ca(2+)-binding proteins, have been described in cells of the epithelial lineage where they are either expressed constitutively (e.g. by mucosal squamous epithelium) or induced during disease (e.g. in keratinocytes during the course of psoriasis). Their biological function, however, is not yet clear. Recent studies have provided evidence that S-100-like proteins may interact with cytoskeletal components; we have therefore studied the biochemical properties and subcellular distribution of MRP8 and MRP14 in epithelial cells. TR146 human squamous carcinoma cells, which were found to express MRP8 and MRP14 in Northern and Western blot studies, were chosen for analysis. Cross-linking experiments using bis(sulphosuccinimidyl)suberate followed by SDS/PAGE and Western blot analysis revealed formation of heteromeric MRP8-MRP14 complexes. On subjecting TR146 cell lysates to two-dimensional gel electrophoresis and Western blotting, four distinct MRP14 isoforms could be identified resembling those described earlier in macrophages. A differential centrifugation technique revealed a Ca(2+)-dependent translocation of MRP8-MRP14 from the cytoplasm to the membrane and the Nonidet P40-insoluble cytoskeletal fraction. Double-label immunofluorescence microscopy of Ca2+ ionophore A23187-stimulated TR146 cells and cytochalasin B and demecolcine cytoskeleton disruption studies identified these structures as keratin intermediate filaments. Ca(2+)-dependent binding of MRP8-MRP14 to keratin filaments was additionally confirmed by an in vitro binding assay. In conclusion, our data suggest that MRP8 and MRP14 may be involved in Ca(2+)-dependent reorganization of cytoskeletal filaments in epithelial cells, which could be of importance for events associated with differentiation and inflammatory activation.

1995-01-01 | S-EPMC1135748 | BioStudies

Expression of the calcium-binding proteins MRP8 and MRP14 in monocytes is regulated by a calcium-induced suppressor mechanism.

Project description:MRP8 and MRP14 are two calcium-binding proteins of the S-100 family the expression of which is restricted to distinct stages of monocytic differentiation. Heteromeric MRP8/MRP14 complexes have been shown to represent their biologically active forms. However, it is not as yet clear whether biochemical modification of complexes, or regulation on the transcriptional level, are responsible for the control of MRP8/MRP14 expression. Employing Western-blot analysis and metabolic labelling we have demonstrated that patterns and metabolism of MRP8/MRP14 complexes do not change during up- or down-regulation of MRP8/MRP14. By Northern-blot analysis it was shown that MRP8/MRP14 are regulated at the transcriptional level rather than by biochemical modification of the complexes. Elevation of intracellular calcium levels by A23187, as well as by thapsigargin, was found to lead to specific down-regulation of MRP8/MRP14 mRNA which is in contrast with data reported for inflammatory factors such as interleukin-1 or tumour necrosis factor alpha. Concomitant application of actinomycin D and calcium ionophore indicated that this suppressive effect is mediated by decreased synthesis rather than increased degradation of MRP8/MRP14 mRNA. Finally, we demonstrated that calcium-mediated down-regulation of MRP8-MRP14 can be antagonized by cycloheximide, suggesting that a calcium-induced repressor protein is responsible for suppression of MRP8-MRP14 at the transcriptional level. Our data indicate that the function of MRP8-MRP14 is restricted to events associated with early stages of myelomonocytic activation.

1994-01-01 | S-EPMC1137038 | BioStudies

Alarmins MRP8 and MRP14 induce stress-tolerance in phagocytes under sterile inflammatory conditions

Project description:Hyporesponsiveness by phagocytes, a well-known phenomenon in sepsis, is frequently induced by low-dose endotoxin-stimulation of Toll-like-receptor-4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins myeloid-related protein (MRP) 8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner resulting in enhanced survival during murine septic shock. Also during sterile inflammation, polytrauma and burn patients present with initially high MRP serum concentrations identifying these proteins as obvious candidates for triggering secondary hyporesponsiveness in these patients. Interestingly, increased peripartal MRP concentrations prime human neonatal phagocytes for hyporesponsiveness, which was confirmed in murine neonatal endotoxinemia in wildtype and MRP14 -/- mice. Using a comparative bioinformatics analysis between genome-wide response patterns of MRP- and LPS- tolerized monocytes we demonstrated no difference in global gene expression between samples pretreated with either MRP8-MRP14 or LPS. Our data indicate that alarmin-triggered phagocyte tolerance represents a novel regulatory mechanism for the susceptibility of neonates to systemic infections and during sterile inflammation. Human blood monocytes prestimulated with MRP8-MRP14 or LPS and afterwards activated with LPS were selected for RNA extraction and hybridization on Illumina microarrays.

| E-GEOD-61477 | BioStudies

The diagnostic and prognostic value of MRP8/MRP14 in intrahepatic cholangiocarcinoma.

Project description:Myeloid-related protein 8 (MRP8) and 14 (MRP14) are abundantly expressed in several kinds of benign and malignant tumors. However, little is known about their clinicopathological significance in intrahepatic cholangiocarcinoma (ICC), biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of bile duct (IPNB), or inflammatory hepatic biliary ducts epithelium (IHBD). This study aimed to investigate the diagnostic and prognostic values of MRP8 and MRP14 as new biomarkers for ICC. We examined MRP8 and MRP14 expression levels by immunohistochemistry in IHBD (n = 15), BilIN (BilIN1 = 24, BilIN2 = 9, BilIN3 = 5), IPNB (n = 18) and ICC (n = 416). The differential diagnostic and prognosis values were also evaluated. The results showed that the ratio of tumor-infiltrating MRP8 and MRP14 positive immune cells, relative to biliary epithelial cells, was significantly increased in ICC tissues compared with nonmalignant tissues, including IHBD, BilIN1, BilIN2, BilIN3, and IPNB (P value < 0.05). In addition, over-expression levels of MRP8 and MRP14 were correlated with overall survival (OS) and time to recurrence (TTR) by univariate analysis; MRP8/MRP14 combination was an independent prognostic factor for OS and TTR. MRP8 and MRP14 expression might help to identify the benign bile duct diseases from ICC, as high expression of MRP8 and MRP14 suggests a poor prognosis after surgical resection.

| S-EPMC4770777 | BioStudies

CD14+ Cells with the Phenotype of Infiltrated Monocytes Consist of Distinct Populations Characterized by Anti-inflammatory as well as Pro-inflammatory Activity in Gouty Arthritis.

Project description:It has been suggested that inflammasome-mediated IL-1? production in monocytic cells is responsible for the acute inflammatory response in gouty arthritis. However, phenotypical and functional analyses of monocytes during gouty arthritis have yet to be conducted. Therefore, we investigated the characteristics of monocytes/macrophages in the synovial fluid cells of patients with acute gout. The number and frequency of monocytes/macrophages in the synovial fluid mononuclear cells (SFMCs) of patients was examined. The expression of markers for monocyte recruitment and tissue-resident macrophages, the production of pro-inflammatory and anti-inflammatory cytokines, and phagocytosis were analyzed in the monocytes/macrophages of patients with acute gout attacks. The number and frequency of CD14+CD3-CD19-CD56- monocytes/macrophages was markedly increased in the SFMCs of patients with gout compared to those of patients with rheumatoid arthritis (RA). CD14+ cells showed the phenotypes of infiltrated monocytes rather than tissue-resident macrophages, characterized by a high expression of CCR2, MRP8, and MRP14, but a low expression of MERTK and 25F9. These cells had the capacity to produce pro-inflammatory cytokines such as TNF-? and IL-1? after stimulation with lipopolysaccharides. In addition, anti-inflammatory features, including CD163 expression and IL-10 production from CD14+ cells, were significantly higher in patients with gout than in those with RA. CD14+ cells with phenotype of M2 macrophages had high phagocytic activity for monosodium urate crystals. Thus, our results indicate that monocytes/macrophages from patients with gout have the phenotype of infiltrated monocytes, and these cells consist of different populations characterized by anti-inflammatory activities as well as pro-inflammatory functions.

| S-EPMC5635328 | BioStudies

Transcription profiling of human HMEC after stimulation with MRP8/MRP14

Project description:GEnerating the the gene expression profil of MRP8/MRP14-stimulated HMEC monolayer. Experiment Overall Design: 4 independent experiments Experiment Overall Design: HMEC-1 monolayer were left untreated or stimulated for 6h with 200 Âµg/ml MRP8/MRP14.

| E-GEOD-5474 | BioStudies

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice.

Project description:BACKGROUND:Depression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression. METHODS:After 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo. RESULTS:Four-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-?B signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia. CONCLUSIONS:These data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.

| S-EPMC6122683 | BioStudies

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