| 1. |
- Mayes, Maureen D, et al.
(författare)
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Immunochip analysis identifies multiple susceptibility Loci for systemic sclerosis.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 94:1, s. 47-61
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Tidskriftsartikel (refereegranskat)abstract
- In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
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| 2. |
- Mihaila, Andreea C., et al.
(författare)
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Transcriptional Profiling and Functional Analysis of N1/N2 Neutrophils Reveal an Immunomodulatory Effect of S100A9-Blockade on the Pro-Inflammatory N1 Subpopulation
- 2021
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils have been classically viewed as a homogenous population. Recently, neutrophils were phenotypically classified into pro-inflammatory N1 and anti-inflammatory N2 sub-populations, but the functional differences between the two subtypes are not completely understood. We aimed to investigate the phenotypic and functional differences between N1 and N2 neutrophils, and to identify the potential contribution of the S100A9 alarmin in neutrophil polarization. We describe distinct transcriptomic profiles and functional differences between N1 and N2 neutrophils. Compared to N2, the N1 neutrophils exhibited: i) higher levels of ROS and oxidative burst, ii) increased activity of MPO and MMP-9, and iii) enhanced chemotactic response. N1 neutrophils were also characterized by elevated expression of NADPH oxidase subunits, as well as activation of the signaling molecules ERK and the p65 subunit of NF-kB. Moreover, we found that the S100A9 alarmin promotes the chemotactic and enzymatic activity of N1 neutrophils. S100A9 inhibition with a specific small-molecule blocker, reduced CCL2, CCL3 and CCL5 chemokine expression and decreased MPO and MMP-9 activity, by interfering with the NF-kB signaling pathway. Together, these findings reveal that N1 neutrophils are pro-inflammatory effectors of the innate immune response. Pharmacological blockade of S100A9 dampens the function of the pro-inflammatory N1 phenotype, promoting the alarmin as a novel target for therapeutic intervention in inflammatory diseases.
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| 3. |
- Boteanu, Raluca Maria, et al.
(författare)
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Short‐Term Blockade of Pro‐Inflammatory Alarmin S100A9 Favorably Modulates Left Ventricle Proteome and Related Signaling Pathways Involved in Post‐Myocardial Infarction Recovery
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:9
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Tidskriftsartikel (refereegranskat)abstract
- Prognosis after myocardial infarction (MI) varies greatly depending on the extent of dam-aged area and the management of biological processes during recovery. Reportedly, the inhibition of the pro‐inflammatory S100A9 reduces myocardial damage after MI. We hypothesize that a S100A9 blockade induces changes of major signaling pathways implicated in post‐MI healing. Mass spectrometry‐based proteomics and gene analyses of infarcted mice left ventricle were performed. The S100A9 blocker (ABR‐23890) was given for 3 days after coronary ligation. At 3 and 7 days post‐ MI, ventricle samples were analyzed versus control and Sham‐operated mice. Blockade of S100A9 modulated the expressed proteins involved in five biological processes: leukocyte cell–cell adhesion, regulation of the muscle cell apoptotic process, regulation of the intrinsic apoptotic signaling pathway, sarco-mere organization and cardiac muscle hypertrophy. The blocker induced regulation of 36 proteins inter-acting with or targeted by the cellular tumor antigen p53, prevented myocardial compensatory hy-pertrophy, and reduced cardiac markers of post‐ischemic stress. The blockade effect was prominent at day 7 post‐MI when the quantitative features of the ventricle proteome were closer to controls. Blockade of S100A9 restores key biological processes altered post‐MI. These processes could be val-uable new pharmacological targets for the treatment of ischemic heart. Mass spectrometry data are available via ProteomeXchange with identifier PXD033683.
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| 4. |
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| 5. |
- Mareş, Răzvan Gheorghiţă, et al.
(författare)
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S100A8/A9 is a valuable biomarker and treatment target to detect and modulate neutrophil involvement in myocardial infarction
- 2023
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Ingår i: Romanian Journal of Morphology and Embryology. - 1220-0522. ; 64:2, s. 151-158
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Tidskriftsartikel (refereegranskat)abstract
- Myocardial infarction (MI) leads to irreversible ischemic damage of the heart muscle and is the leading cause of heart failure. The ischemic cardiac injury triggers a potent local and systemic immune response. In the acute phase post-MI, neutrophils infiltrate the myocardium in large numbers and induce further cardiomyocyte death, expanding the infarcted area. The alarmin S100A8/A9 is a proinflammatory mediator primarily produced by myeloid cells, with an emerging role in MI. We previously demonstrated that short-term inhibition of S100A8/A9 during the inflammatory phase of the immune response to MI improves long-term cardiac function. In the present study, we investigated the effects of S100A8/A9 blockade on myocardial inflammation and post-ischemic myocardial injury in a mouse model of coronary artery ligation. Immunohistochemical (IHC) staining revealed that the presence of S100A9 is strongly correlated with neutrophil infiltration in the myocardium on days 1 and 3 post-MI. A 3-day treatment with the S100A8/A9 blocker ABR-238901 starting immediately after MI decreased the number of neutrophils and S100A9 presence in the myocardium and had a positive impact on cardiac damage, reducing infarction size. These findings promote S100A9 as an IHC biomarker of neutrophil infiltration and a promising immunomodulatory target to regulate neutrophil recruitment, reduce ischemic injury and promote long-term beneficial cardiac recovery after MI.
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| 6. |
- Mares, Razvan Gheorghita, et al.
(författare)
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Studying the innate immune response to myocardial infarction in a highly efficient experimental animal model
- 2021
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Ingår i: Revista Romana de Cardiologie. - : Walter de Gruyter GmbH. - 1220-658X. ; 31:3, s. 573-585
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Tidskriftsartikel (refereegranskat)abstract
- The reduction in mortality following acute myocardial infarction (AMI) is an important achievement of modern medicine. Despite this progress, AMI remains the most common cause of heart failure (HF) and HF-related morbidity and mortality. The involvement of the innate immune response in different stages after AMI has attracted important attention in recent years. With the increasing range of potential therapeutic compounds and delivery vectors, the need of highly efficient experimental AMI models is increasing, to support further advancement in this field. Here, we present a high-throughput model for the assessment of the innate immune response to AMI. The model is based on permanent surgical ligation of the left descending coronary artery (LAD) in mice, followed by complex flow-cytometry and histological analyses of immune cellular populations in blood and myocardium. We are presenting time-dependent qualitative and quantitative analysis results, demonstrating intense accumulation of Ly6Ghi neutrophils and Ly6Chi monocytes in the infarcted myocardium on days 1 and 3 post-AMI, followed by successive accumulation of reparatory Ly6CloMerTKhi macrophages, neovascularization and fibrosis development by day 7.
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