leukocyte activation
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2021 ◽  
Vol 79 (3) ◽  
pp. 395-406
Author(s):  
Georg Hagn ◽  
Bruce Holbein ◽  
Juan Zhou ◽  
Christian Lehmann

BACKGROUND: Interstitial cystitis (IC) is a prevalent and debilitating chronic inflammatory disease of the urinary bladder. Currently there are no fully effective therapeutic agents available, in part due to the still obscure pathogenesis of IC. Lipopolysaccharide (LPS) also known as endotoxin from Gram negative bacteria elicits IC in mice and has formed the basis of model systems for investigation. Excess free iron plays an important role in inflammation through generation of reactive oxygen species (ROS). The novel iron chelator DIBI has been shown to sequester excess free iron and dampen excess inflammatory responses to systemic LPS administration and also to Gram negative bacterial infections. OBJECTIVE: The overall objective of this study was to evaluate the effects of DIBI on LPS induced IC in mice. Leukocyte activation, endothelial adhesion and functional capillary density were assessed by intravital microscopy of the bladder microcirculation following a single intravesical LPS administration with or without intravesical DIBI treatment. Clinical IC symptoms were also assessed through behavioral and pain threshold force measurements. METHODS: Four groups of female BALB/c mice (n = 5–6/group) were randomized in this study: control group, IC group without therapy, IC group with DIBI therapy and control group with DIBI therapy. The groups were examined using intravital microscopy (IVM) of the bladder for leukocyte-endothelial interactions (adherent leukocytes, temporarily interacting leukocytes) and functional capillary density (FCD). A modified behavioral score by Boucher et al. and Von-Frey-Aesthesiometry were used to evaluate key behavioral indices related to pain and visceral pain perception. RESULTS: LPS introduced intravesically induced an early (≤2h) inflammation of the bladder evidenced by leukocyte activation and adhesion to bladder capillary walls. Intravesical DIBI therapy of mice 30min following LPS administration and assessed after 1.5h treatment showed a significant decrease in the number of adherent leukocytes compared to IC animals without DIBI treatment. DIBI treated mice showed a significantly lowered increase in behavioral distress scores compared to IC mice without therapy. Untreated IC mice exhibited a significantly decreased threshold force value for evoked pain response and DIBI treatment improved the threshold pain response. A significant inverse correlation was found for the two pain and suffering evaluation methods results. CONCLUSION: DIBI reduced inflammatory endothelial leukocyte adhesion and key indices related to pain and suffering over those observed in untreated IC mice. Our findings suggest a potential therapeutic role for DIBI for IC treatment.


2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Yue Zheng ◽  
Yijie Gong ◽  
Yuheng Lang ◽  
Zhenchang Qi ◽  
Xiaomin Hu ◽  
...  

Young patients with type 2 diabetes and myocardial infarction (MI) have higher long-term all-cause and cardiovascular mortality. In addition, the observed increased, mildly abnormal baseline lipid levels, but not lipid variability, are associated with an increased risk of atherosclerotic cardiovascular disease events, particularly MI. This study investigated differentially expressed genes (DEGs), which might be potential targets for young patients with MI and a high-fat diet (HFD). GSE114695 and GSE69187 were downloaded and processed using the limma package. A Venn diagram was applied to identify the same DEGs, and further pathway analysis was performed using Metascape. Protein-protein interaction (PPI) network analysis was then applied, and the hub genes were screened out. Pivotal miRNAs were predicted and validated using the miRNA dataset in GSE114695. To investigate the cardiac function of the screened genes, an MI mouse model, echocardiogram, and ELISA of hub genes were applied, and a correlation analysis was also performed. From aged mice fed HFD, 138 DEGs were extracted. From aged mice fed with chow, 227 DEGs were extracted. Pathway enrichment analysis revealed that DEGs in aging mice fed HFD were enriched in lipid transport and lipid biosynthetic process 1 d after MI and in the MAPK signaling pathway at 1 w after MI, suggesting that HFD has less effect on aging with MI. A total of 148 DEGs were extracted from the intersection between plaques fed with HFD and chow in young mice and MI_1d, respectively, which demonstrated increased inflammatory and adaptive immune responses, in addition to myeloid leukocyte activation. A total of 183 DEGs were screened out between plaques fed with HFD vs. chow in young mice and MI_1w, respectively, which were mainly enriched in inflammatory response, cytokine production, and myeloid leukocyte activation. After validation, PAK3, CD44, CD5, SOCS3, VAV1, and PIK3CD were demonstrated to be negatively correlated with LVEF; however, P2RY1 was demonstrated to be positively correlated. This study demonstrated that the screened hub genes may be therapeutic targets for treating STEMI patients and preventing MI recurrence, especially in young MI patients with HFD or diabetes.


2021 ◽  
Author(s):  
Visnu Chaparro ◽  
Tyson E. Graber ◽  
Tommy Alain ◽  
Maritza Jaramillo

Abstract Macrophages undergo swift changes in mRNA abundance upon pathogen invasion. Herein we describe early remodelling of the macrophage transcriptome during infection by amastigotes or promastigotes of Leishmania donovani. Approximately 10% - 16% of host mRNAs were differentially modulated in L. donovani-infected macrophages when compared to uninfected controls. This response was partially stage-specific as a third of changes in mRNA abundance were either exclusively driven by one of the parasite forms or significantly different between them. Gene ontology analyses identified categories associated with immune functions (e.g. antigen presentation and leukocyte activation) among significantly downregulated mRNAs while cytoprotective-related categories (e.g. DNA repair and apoptosis inhibition) were enriched in upregulated transcripts during amastigote infection. Interestingly a combination of upregulated (e.g. cellular response to IFNβ) and repressed (e.g. leukocyte activation, chemotaxis) immune-related transcripts were overrepresented in the promastigote-infected dataset. In addition, Ingenuity Pathway Analysis (IPA®) coupled specific mRNA subsets with a number of upstream transcriptional regulators predicted to be modulated in macrophages infected with L. donovani amastigotes (e.g. STAT1 inhibition) or promastigotes (e.g. NRF2, IRF3, and IRF7 activation). Overall, our results indicate that early parasite stage-driven transcriptional remodelling in macrophages contributes to orchestrate both protective and deleterious host cell responses during L. donovani infection.


2021 ◽  
Vol 10 (17) ◽  
pp. 3907
Author(s):  
Salim S. Hayek ◽  
Christoph Roderburg ◽  
Pennelope Blakely ◽  
Christopher Launius ◽  
Jesper Eugen-Olsen ◽  
...  

Background: Severe coronavirus disease 2019 (COVID-19) is the result of a hyper-inflammatory reaction to the severe acute respiratory syndrome coronavirus 2. The biomarkers of inflammation have been used to risk-stratify patients with COVID-19. Osteopontin (OPN) is an integrin-binding glyco-phosphoprotein involved in the modulation of leukocyte activation; its levels are associated with worse outcomes in patients with sepsis. Whether OPN levels predict outcomes in COVID-19 is unknown. Methods: We measured OPN levels in serum of 341 hospitalized COVID-19 patients collected within 48 h from admission. We characterized the determinants of OPN levels and examined their association with in-hospital outcomes; notably death, need for mechanical ventilation, and need for renal replacement therapy (RRT) and as a composite outcome. The risk discrimination ability of OPN was compared with other inflammatory biomarkers. Results: Patients with COVID-19 (mean age 60, 61.9% male, 27.0% blacks) had significantly higher levels of serum OPN compared to healthy volunteers (96.63 vs. 16.56 ng/mL, p < 0.001). Overall, 104 patients required mechanical ventilation, 35 needed dialysis, and 53 died during their hospitalization. In multivariable analyses, OPN levels ≥140.66 ng/mL (third tertile) were associated with a 3.5 × (95%CI 1.44–8.27) increase in the odds of death, and 4.9 × (95%CI 2.48–9.80) increase in the odds of requiring mechanical ventilation. There was no association between OPN and need for RRT. Finally, OPN levels in the upper tertile turned out as an independent prognostic factor of event-free survival with respect to the composite endpoint. Conclusion: Higher OPN levels are associated with increased odds of death and mechanical ventilation in patients with COVID-19, however, their utility in triage is questionable.


2021 ◽  
Vol 12 ◽  
Author(s):  
Clement Triaille ◽  
Patrick Durez ◽  
Tatiana Sokolova ◽  
Gaëlle Tilman ◽  
Laurent Méric de Bellefon ◽  
...  

ObjectivesOur goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.MethodsSynovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.ResultsGene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.ConclusionWe provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.


Author(s):  
Kruthi Suvarna ◽  
Akanksha Salkar ◽  
Viswanthram Palanivel ◽  
Renuka Bankar ◽  
Nirjhar Banerjee ◽  
...  

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Ning Liu ◽  
Jinrui Han ◽  
Yadan Li ◽  
Yinghua Jiang ◽  
Samuel X. Shi ◽  
...  

Abstract Background Traumatic brain injury (TBI) is a significant cause of death and disability worldwide. The TLR4-NFκB signaling cascade is the critical pro-inflammatory activation pathway of leukocytes after TBI, and modulating this signaling cascade may be an effective therapeutic target for treating TBI. Previous studies indicate that recombinant annexin A2 (rA2) might be an interactive molecule modulating the TLR4-NFκB signaling; however, the role of rA2 in regulating this signaling pathway in leukocytes after TBI and its subsequent effects have not been investigated. Methods C57BL/6 mice were subjected to TBI and randomly divided into groups that received intraperitoneal rA2 or vehicle at 2 h after TBI. The peripheral leukocyte activation and infiltrating immune cells were examined by flow cytometry, RT-qPCR, and immunostaining. The neutrophilic TLR4 expression on the cell membrane was examined by flow cytometry and confocal microscope, and the interaction of annexin A2 with TLR4 was assessed by co-immunoprecipitation coupled with Western blotting. Neuroinflammation was measured via cytokine proteome profiler array and RT-qPCR. Neurodegeneration was determined by Western blotting and immunostaining. Neurobehavioral assessments were used to monitor motor and cognitive function. Brain tissue loss was assessed via MAP2 staining. Results rA2 administration given at 2 h after TBI significantly attenuates neutrophil activation and brain infiltration at 24 h of TBI. In vivo and in vitro data show that rA2 binds to and reduces TLR4 expression on the neutrophil surface and suppresses TLR4/NFκB signaling pathway in neutrophils at 12 h after TBI. Furthermore, rA2 administration also reduces pro-inflammation of brain tissues within 24 h and neurodegeneration at 48 h after TBI. Lastly, rA2 improves long-term sensorimotor ability and cognitive function, and reduces brain tissue loss at 28 days after TBI. Conclusions Systematic rA2 administration at 2 h after TBI significantly inhibits activation and brain infiltration of peripheral leukocytes, especially neutrophils at the acute phase. Consequently, rA2 reduces the detrimental brain pro-inflammation-associated neurodegeneration and ultimately ameliorates neurological deficits after TBI. The underlying molecular mechanism might be at least in part attributed to rA2 bindings to pro-inflammatory receptor TLR4 in peripheral leukocytes, thereby blocking NFκB signaling activation pathways following TBI.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 20.1-20
Author(s):  
C. Triaille ◽  
T. Gaelle ◽  
T. Sokolova ◽  
L. Meric de Bellefon ◽  
C. Galant ◽  
...  

Background:Modes of action of DMARDs (disease-modifying antirheumatic drugs) in rheumatoid arthritis (RA) are not completely understood at the level of the synovium. Studying treatment-induced modifications in RA synovial tissue can provide unique insights into the pathways modulated downstream of different DMARDs.Objectives:Our goal was to assess histological and transcriptomic effects of Abatacept (ABA) on RA synovium, and to compare them with previously published data obtained by our group using the same study design on other DMARDs: Tocilizumab (TCZ), Rituximab (RTX), Methotrexate (MTX) and Adalimumab (ADA).Methods:Synovial tissue was obtained using ultrasound-guided biopsy from affected joints before (W0) and 16 weeks (W16) after treatment with subcutaneous Abatacept 125mg per week on a MTX background. Paraffin-sections were stained for CD3, CD20 and CD68 and scored by a pathologist for T cell, B cell and macrophage infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix), and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape (https://metascape.org/) and EnrichR (https://maayanlab.cloud/Enrichr/). Protein-Protein Interaction (PPI) networks were generated on STRING (https://string-db.org/).Results:14 RA patients were included (female: 9, ACPA/RF positive: 8, erosive disease: 12, median disease duration in years (± SD): 11.7 (± 8.1), median DAS28CRP (± SD): 4.78 (± 1.11)). Median DAS28CRP significantly decreased between W0 and W16, as did US GS score. Evaluation of histological slides (n=11 pairs of samples) showed no significant effect of Abatacept on T cell, B cell or macrophage infiltration. Gene expression analysis (n=10 pairs of samples) identified 304 transcripts differentially expressed (129 downregulated, 175 upregulated) between W0 and W16 (FC≥1.5 and p<0.05, paired Mann-Whitney). Downregulated genes were significantly enriched for immune processes and included several key T cell regulatory genes (IL2RA, CD28, IL7, IL7R), strongly overlapping with data from previous studies on TCZ (n= 12 pairs), RTX (n=12 pairs), MTX (n=8 pairs) and ADA (n=8 pairs). Thus, each treatment shares 31 to 48% of its downregulated genes with the others, with genes downregulated by at least three involved in key RA-associated pathways such as leukocyte activation, NF-kappa B signaling, TNF signaling and JAK-STAT signaling. Given their seemingly overlapping effects, data were pooled across these studies, markedly improving power thanks to their paired-design. This revealed that genes downregulated by DMARDs (n=573, Benjamini-Hochberg corrected p-value<0.05, paired Mann-Whitney) were significantly enriched for both T cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have a coordinate effect on the two pathways (correlation of mean Log2FC: r=0.8558, p<0.0001), with a stronger impact (Log2FCW16-W0) in good responders to therapy (n=17) as compared to moderate (n=20) and to non-responders (n=13) (p<0.0001, Mann-Whitney). Finally, Transcription Factor enrichment and PPI network analyses point to a central role for molecules including JAK/STATs as mediators of all studied therapies.Conclusion:We provide evidence that the effects of five DMARDs on RA synovium culminate in the same pathways (namely, T cell and myeloid leukocyte activation). This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets, and suggests attractive new therapeutic targets.Acknowledgements:This work was funded in part by unrestricted grants from Cap48 (RTBF) and Bristol-Myers Squibb. Clément Triaille is funded by the Fonds National de la Recherche Scientifique (FNRS, Communauté française de Belgique) and Fondation Saint-Luc (Cliniques Universitaires Saint-Luc).Disclosure of Interests:Clément Triaille: None declared, Tilman Gaelle: None declared, Tatiana Sokolova: None declared, Laurent Meric de Bellefon: None declared, Christine Galant: None declared, Patrick Durez Grant/research support from: unrestricted research grant from Bristol-Myers Squibb, Bernard Lauwerys Employee of: currently employed at UCB Biopharma, Nisha Limaye: None declared


Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 582
Author(s):  
Hai Deng ◽  
Ting-Xuan Tang ◽  
Deng Chen ◽  
Liang-Sheng Tang ◽  
Xiang-Ping Yang ◽  
...  

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has been recently considered a systemic disorder leading to the procoagulant state. Preliminary studies have shown that SARS-CoV-2 can infect endothelial cells, and extensive evidence of inflammation and endothelial dysfunction has been found in advanced COVID-19. Endothelial cells play a critical role in many physiological processes, such as controlling blood fluidity, leukocyte activation, adhesion, platelet adhesion and aggregation, and transmigration. Therefore, it is reasonable to think that endothelial dysfunction leads to vascular dysfunction, immune thrombosis, and inflammation associated with COVID-19. This article summarizes the association of endothelial dysfunction and SARS-CoV-2 infection and its therapeutic strategies.


2021 ◽  
Vol 3 (5) ◽  
pp. e0394
Author(s):  
Anuradha Ramoji ◽  
Daniel Thomas-Rüddel ◽  
Oleg Ryabchykov ◽  
Michael Bauer ◽  
Natalie Arend ◽  
...  

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