Systemic IL-15, IFN-γ, and IP-10/CXCL10 signature associated with effective immune response to SARS-CoV-2 in BNT162b2 mRNA vaccine recipients.
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ABSTRACT:
SUBMITTER: Bergamaschi C
PROVIDER: S-EPMC8299183 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In tonsils, CD138(+) plasma cells (PCs) are surrounded by CD163(+) resident macrophages (Ms). We show here that human Ms (isolated from tonsils or generated from monocytes in vitro) drive activated B cells to differentiate into CD138(+)CD38(++) PCs through secreted CXCL10/IP-10 and VCAM-1 contact. IP-10 production by Ms is induced by B cell-derived IL-6 and depends on STAT3 phosphorylation. Furthermore, IP-10 amplifies the production of IL-6 by B cells, which sustains the STAT3 signals that lead to PC differentiation. IP-10-deficient mice challenged with NP-Ficoll show a decreased frequency of NP-specific PCs and lower titers of antibodies. Thus, our results reveal a novel dialog between Ms and B cells, in which IP-10 acts as a PC differentiation factor.
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Project description: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-γ 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-κB 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-κB 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.
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Project description:BackgroundThe inflammatory chemokine, interferon-gamma inducible protein of 10kDa (IP-10), is a biomarker associated with several conditions.ObjectivesThis study investigated serum concentrations of IP-10 in healthy individuals who developed acute respiratory infection (ARI). The hypothesis is that serum IP-10 concentrations correlate with ARI severity and detection of viral pathogens.Study designData come from a randomized controlled trial measuring the effects of mindfulness meditation or exercise on ARI (Clinical Trials ID: NCT01654289). Healthy adults ages 30-69 were followed for a single season for ARI incidence and severity. This trial is ongoing, and the investigators are still blinded. When a participant reported ARI symptoms, nasal swab and lavage for PCR-based viral identification and blood samples were collected within the first 72h of ARI symptoms. Serum IP-10 concentrations were measured by ELISA (R&D Systems, Inc., Quantikine ELISA, Minneapolis, MN). ARI severity was measured using the validated Wisconsin Upper Respiratory Symptom Survey (WURSS-24) until the ARI episode resolved.ResultsSerum IP-10 concentrations from 225 ARI episodes correlated with ARI global severity (rho 0.28 [95% CI: 0.15-0.39]; p<0.001). IP-10 concentrations were higher with an ARI in which a viral pathogen was detected compared to no viral pathogen detected (median 366pg/ml [IQR: 227-486] vs 163pg/ml [IQR: 127-295], p<0.0001). Influenza infections had higher IP-10 concentrations than coronavirus, enterovirus or rhinovirus, and paramyxovirus.ConclusionSerum IP-10 concentration correlates with ARI global severity. Also, IP-10 concentration measured early in the course of the ARI correlates with the daily severity, duration, and illness symptoms.
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Project description:BackgroundPleural tuberculosis (PlTB) is the most common extrapulmonary manifestation of this infectious disease which still presents high mortality rates worldwide. Conventional diagnostic tests for PlTB register multiple limitations, including the lack of sensitivity of microbiological methods on pleural specimens and the need of invasive procedures such as pleural biopsy performance. In this scenario, the search for biological markers on pleural fluid (PF) has been the target of several studies as a strategy to overcome the limitations of PlTB diagnosis. This study aims to evaluate the use either isolated or in combination with adenosine deaminase (ADA), interferon-gamma (IFN-γ), interferon-gamma inducible protein of 10-kD (IP-10) levels on PF in order to guide an accurate anti-TB treatment in microbiologically non-confirmed cases.Methods and findingsEighty patients presenting pleural effusion under investigation were enrolled in a cross-sectional study conducted at Pedro Ernesto University Hospital, Rio de Janeiro, RJ, Brazil. Peripheral blood (PB) and PF samples collected from all patients were applied to the commercial IFN-γ release assay, QuantiFERON-TB Gold In-Tube, and samples were analyzed for IFN-γ and IP-10 by immunoassays. ADA activity was determined on PF by the colorimetric method. Based on microbiological and histological criteria, patients were categorized as follow: confirmed PlTB (n = 16), non-confirmed PlTB (n = 17) and non-PlTB (n = 47). The Mycobacterium tuberculosis antigen-specific production of IFN-γ and IP-10 on PB or PF did not show significant differences. However, the basal levels of these biomarkers, as well as the ADA activity on PF, were significantly increased in confirmed PlTB in comparison to non-PlTB group. Receiver operating characteristics curves were performed and the best cut-off points of these three biomarkers were estimated. Their either isolated or combined performances (sensitivity [Se], specificity [Sp], positive predictive value [PPV], negative predictive value [NPV] and accuracy [Acc]) were determined and applied to Venn's diagrams among the groups. Based on the confirmed PlTB cases, IFN-γ showed the best performance of them at a cut-off point of 2.33 IU/mL (Se = 93.8% and Sp = 97.9%) followed by ADA at a cut-off of 25.80 IU/L (Se = 100% and Sp = 84.8%) and IP-10 (Cut-point = 4,361.90 pg/mL, Se = 75% and Sp = 82.6%). IFN-γ plus ADA (cut-point: 25.80 IU/L) represent the most accurate biomarker combination (98.4%), showing Se = 93.7%, Sp = 100%, PPV = 100% and NPV = 97.9%. When this analysis was applied in non-confirmed PlTB, 15/17 (88.2%) presented at least two positive biomarkers in combination.ConclusionIFN-γ, IP-10, and ADA in PlTB effusions are significantly higher than in non-PlTB cases. IFN-γ is an excellent rule-in and rule-out test compared to IP-10 and ADA. The combination of IFN-γ and ADA, in a reviewed cut-off point, showed to be particularly useful to clinicians as their positive results combined prompts immediate treatment for TB while both negative results suggest further investigation.
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Project description:Melanoma is the most aggressive skin-cancer, showing high mortality at advanced stages. Platelet Derived Growth Factor Receptor-alpha (PDGFR-alpha) potently inhibits melanoma- and endothelium-proliferation and its expression is significantly reduced in melanoma-biopsies, suggesting that melanoma progression eliminates cells expressing PDGFR-alpha. In the present study transient overexpression of PDGFR-alpha in endothelial (HUVEC) and melanoma (SKMel-28, A375, Preyer) human-cells shows strong anti-proliferative effects, with profound transcriptome and miRNome deregulation. PDGFR-alpha overexpression strongly affects expression of 82 genes in HUVEC (41 up-, 41 down-regulated), and 52 genes in SKMel-28 (43 up-, 9 down-regulated). CXCL10/IP-10 transcript showed up to 20 fold-increase, with similar changes detectable at the protein level. miRNA expression profiling in cells overexpressing PDGFR-alpha identified 14 miRNAs up- and 40 down-regulated, with miR-503 being the most down-regulated (6.4 fold-reduction). miR-503, miR-630 and miR-424 deregulation was confirmed by qRT-PCR. Interestingly, the most upregulated transcript (i.e., CXCL10/IP-10) was a validated miR-503 target and CXCL10/IP-10 neutralization significantly reverted the anti-proliferative action of PDGFR-alpha, and PDGFR-alpha inhibition by Dasatinb totally reverted the CXCL10/IP10 induction, further supporting a functional interplay of these factors. Finally, integration of transcriptomics and miRNomics data highlighted several pathways affected by PDGFR-alpha.This study demonstrates for the first time that PDGFR-alpha strongly inhibits endothelial and melanoma cells proliferation in a CXCL10/IP-10 dependent way, via miR-503 down-regulation.
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Project description:The role of C-X-C motif chemokine 10 (CXCL10), a pro-inflammatory factor, in the development of acute respiratory distress syndrome (ARDS) remains unclear. In this study, we explored the role of CXCL10 and the effect of CXCL10 neutralization in lipopolysaccharide (LPS)-induced ARDS in rats. The expression of CXCL10 and its receptor chemokine receptor 3(CXCR3) increased after LPS induction. Moreover, neutralization of CXCL10 ameliorated the severity of ARDS by reducing pulmonary edema, inhibiting the release of inflammatory mediators (IFN-γ, IL-6 and ICAM-1) and limiting inflammatory cells (neutrophils, macrophages, CD8+ T cells) influx into the lung, with a reduction in CXCR3 expression in neutrophils and macrophages. Therefore, CXCL10 could be a potential therapeutic target in LPS-induced ARDS.
| S-EPMC5207674 | biostudies-literature
Project description:Biomarkers of chronic inflammation (such as C-reactive protein) have long been associated with cardiovascular disease and mortality; however, biomarkers involved in antiviral cytokine induction and adaptive immune system activation remain largely unexamined. We hypothesized the cytokine interferon gamma inducible protein 10 (IP-10) would be associated with clinical and subclinical cardiovascular disease and all-cause mortality in African Americans. We assessed these associations in the Jackson Heart Study (JHS) cohort and the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. There was a modest association of IP-10 with higher odds of left ventricular hypertrophy (OR = 1.20 (95% confidence interval (CI) 1.03, 1.41) per standard deviation (SD) higher natural log-transformed IP-10 in JHS). We did not observe associations with ankle brachial index, intima-media thickness, or arterial calcification. Each SD higher increment of ln-transformed IP-10 concentration was associated with incident heart failure (hazard ratio (HR) 1.26; 95% CI 1.11, 1.42, p = 4x10-4) in JHS, and with overall mortality in both JHS (HR 1.12 per SD, 95% CI 1.03, 1.21, p = 7.5x10-3) and REGARDS (HR 1.31 per SD, 95% CI 1.10, 1.55, p = 2.0 x 10-3), adjusting for cardiovascular risk factors and C-reactive protein. However, we found no association between IP-10 and stroke or coronary heart disease. These results suggest a role of IP-10 in heart failure and mortality risk independent of C-reactive protein. Further research is needed to investigate how the body's response to chronic viral infection may mediate heart failure and overall mortality risk in African Americans.
| S-EPMC7117698 | biostudies-literature
Project description:BackgroundLupus nephritis (LN) is a prevalent and severe complication of systemic lupus erythematosus (SLE). Non-invasive diagnostics are limited, and current therapies have inadequate response rates. Expression of the chemokine Interferon-γ-induced protein 10 (IP-10) is regulated by Interferon-γ signaling and NF-κB, and its molecular activity and enhanced urine concentrations are implicated in LN, but its utility as a diagnostic marker and association with demographic, clinical, or pathologic features is not defined.Methods38 LN patients and 11 patients with non-LN glomerular diseases (GD) with active disease were included. Eighteen of the LN patients had achieved remission at one follow-up during the study time. Serum and urine were obtained from these samples, and the IP-10 levels were measured.ResultsSerum and urine IP-10 levels are significantly enhanced in LN patients with active disease as compared with normal individuals (serum average 179.7 pg/mL vs. 7.2 pg/mL, p < 0.0001; urine average 28.7 pg/mg vs. 1.6 pg/mg, p = 0.0019) and patients with other forms of glomerular disease (serum average 179.7 pg/mL vs. 84.9 pg/mL, p = 0.0176; urine average 28.7 pg/mg vs. 0.18 pg/mg, p = 0.0011). Urine IP-10 levels are significantly higher in patients with proliferative LN (PLN) than those with membranous LN (MLN) (average 32.8 pg/mg vs. 7.6 pg/mg, p = 0.0155). Urine IP-10 levels are also higher in MLN versus primary membranous nephropathy (MN) (average 7.6 pg/mg vs. 0.2 pg/mg, p = 0.0193). Importantly, serum IP-10 levels remain elevated during active LN and LN remission, but urine IP-10 levels are decreased from active LN to remission in 72% of our patients. Lastly, serum, but not urine IP-10 levels are significantly higher in African American than White American LN patients in active LN (average 227.8 pg/mL vs. 103.4 pg/mL, p = 0.0309) and during LN remission (average 254.6 pg/mL vs. 89.2 pg/mL, p = 0.0399).ConclusionsOur findings suggest that serum and urine IP-10 measurements provide promising tests for monitoring LN activity, differentiation between classifications of LN, and differentiation between LN and other forms of glomerular disease. We also conclude that further assessment of elevated IP-10 levels in the serum and urine of high-risk populations (i.e., African American) could be beneficial in determining why many of these patients have worse outcomes and are non-responsive to standard therapeutics.
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