leukocyte adhesion
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Author(s):  
Luca Massimino ◽  
Salvatore Spanò ◽  
Luigi Antonio Lamparelli ◽  
Davide Fuggetta ◽  
Laurent Peyrin-Biroulet ◽  
...  

Lay Summary The JAK/STAT inhibitor tofacitinib, recently approved for the treatment of ulcerative colitis, is found to modulate the intestinal endothelial barrier functions in directing the leukocyte adhesion and transmigration in ulcerative colitis patients displaying high levels of endothelial STAT3/STAT6 phosphorylation.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Ekaterina Olkhov-Mitsel ◽  
Anjelica Hodgson ◽  
Stan K. Liu ◽  
Danny Vesprini ◽  
Jane Bayani ◽  
...  

AbstractTumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.


2022 ◽  
Vol 12 ◽  
Author(s):  
Yang Ye ◽  
Quan Li ◽  
Chun-Shui Pan ◽  
Li Yan ◽  
Kai Sun ◽  
...  

Background: Thrombolysis with tissue plasminogen activator (tPA) remains the only approved drug therapy for acute ischemic stroke. However, delayed tPA treatment is associated with an increased risk of brain hemorrhage. In this study, we assessed whether QiShenYiQi (QSYQ), a compound Chinese medicine, can attenuate tPA-induced brain edema and hemorrhage in an experimental stroke model.Methods: Male mice were subjected to ferric chloride-induced carotid artery thrombosis followed by mechanical detachment of thrombi. Then mice were treated with QSYQ at 2.5 h followed by administration of tPA (10 mg/kg) at 4.5 h. Hemorrhage, infarct size, neurological score, cerebral blood flow, Evans blue extravasation, FITC-labeled albumin leakage, tight and adherens junction proteins expression, basement membrane proteins expression, matrix metalloproteinases (MMPs) expression, leukocyte adhesion, and leukocyte infiltration were assessed 24 h after tPA administration.Results: Compared with tPA alone treatments, the combination therapy of QSYQ and tPA significantly reduced hemorrhage, infarction, brain edema, Evans blue extravasation, albumin leakage, leukocyte adhesion, MMP-9 expression, and leukocyte infiltration at 28.5 h after stroke. The combination also significantly improved the survival rate, cerebral blood flow, tight and adherens junction proteins (occludin, claudin-5, junctional adhesion molecule-1, zonula occludens-1, VE-cadherin, α-catenin, β-catenin) expression, and basement membrane proteins (collagen IV, laminin) expression. Addition of QSYQ protected the downregulated ATP 5D and upregulated p-Src and Caveolin-1 after tPA treatment.Conclusion: Our results show that QSYQ inhibits tPA-induced brain edema and hemorrhage by protecting the blood-brain barrier integrity, which was partly attributable to restoration of energy metabolism, protection of inflammation and Src/Caveolin signaling activation. The present study supports QSYQ as an effective adjunctive therapy to increase the safety of delayed tPA thrombolysis for ischemic stroke.


Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 138
Author(s):  
Devasahayam Arokia Balaya Rex ◽  
Yashwanth Subbannayya ◽  
Prashant Kumar Modi ◽  
Akhina Palollathil ◽  
Lathika Gopalakrishnan ◽  
...  

Interleukin-33 (IL-33), a member of the IL-1 superfamily cytokines, is an endogenous danger signal and a nuclear-associated cytokine. It is one of the essential mediators of both innate and adaptive immune responses. Aberrant IL-33 signaling has been demonstrated to play a defensive role against various infectious and inflammatory diseases. Although the signaling responses mediated by IL-33 have been previously reported, the temporal signaling dynamics are yet to be explored. To this end, we applied quantitative temporal phosphoproteomics analysis to elucidate pathways and proteins induced by IL-33 in THP-1 monocytes. Employing a TMT labeling-based quantitation and titanium dioxide (TiO2)-based phosphopeptide enrichment strategy followed by mass spectrometry analysis, we identified and quantified 9448 unique phosphopeptides corresponding to 3392 proteins that showed differential regulation. Of these, 171 protein kinases, 60 phosphatases and 178 transcription factors were regulated at different phases of IL-33 signaling. In addition to the confirmed activation of canonical signaling modules including MAPK, NFκB, PI3K/AKT modules, pathway analysis of the time-dependent phosphorylation dynamics revealed enrichment of several cellular processes, including leukocyte adhesion, response to reactive oxygen species, cell cycle checkpoints, DNA damage and repair pathways. The detailed quantitative phosphoproteomic map of IL-33 signaling will serve as a potentially useful resource to study its function in the context of inflammatory and pathological conditions.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 72
Author(s):  
Denise Eckert ◽  
Felicitas Rapp ◽  
Ayele T. Tsedeke ◽  
Jessica Molendowska ◽  
Robert Lehn ◽  
...  

Anti-inflammatory effects of low-dose irradiation often follow a non-linear dose–effect relationship. These characteristics were also described for the modulation of leukocyte adhesion to endothelial cells. Previous results further revealed a contribution of reactive oxygen species (ROS) and anti-oxidative factors to a reduced leukocyte adhesion. Here, we evaluated the expression of anti-oxidative enzymes and the transcription factor Nrf2 (Nuclear factor-erythroid-2-related factor 2), intracellular ROS content, and leukocyte adhesion in primary human microvascular endothelial cells (HMVEC) upon low-dose irradiation under physiological laminar shear stress or static conditions after irradiation with X-ray or Carbon (C)-ions (0–2 Gy). Laminar conditions contributed to increased mRNA expression of anti-oxidative factors and reduced ROS in HMVEC following a 0.1 Gy X-ray and 0.5 Gy C-ion exposure, corresponding to reduced leukocyte adhesion and expression of adhesion molecules. By contrast, mRNA expression of anti-oxidative markers and adhesion molecules, ROS, and leukocyte adhesion were not altered by irradiation under static conditions. In conclusion, irradiation of endothelial cells with low doses under physiological laminar conditions modulates the mRNA expression of key factors of the anti-oxidative system, the intracellular ROS contents of which contribute at least in part to leucocyte adhesion, dependent on the radiation source.


2021 ◽  
Author(s):  
Anam Tasneem ◽  
Shubham Parashar ◽  
Tanya Jain ◽  
Simran Aittan ◽  
Jyoti Rautela ◽  
...  

Cell surface glycans, depending on their structures and dynamic modifications, act as the first point of contact and regulate cell-cell, cell-matrix, and cell-pathogen interactions. Particularly, the sialyl-Lewis-X (sLeX, CD15s) tetrasaccharide epitope, expressed on both glycoproteins and gangliosides, participates in leukocyte extravasation via interactions with selectins expressed on endothelial cells, lymphocytes, and platelets (CD62-E/L/P). Neutrophils carrying sLeX epitopes are thought to be responsible for chronic inflammatory diseases resulting in plaque formation and atherosclerosis. Intense efforts have been devoted to the development of sLeX mimetics for inhibition of cell adhesion. On the other hand, dysregulated expression of sLeX and poor extravasation are the major underlying causes of leukocyte adhesion deficiency-II (LAD-II) disorders that result in frequent infections and poor immune response. We hypothesized that metabolic processing of peracetyl N-(cycloalkyl)acyl-D-mannosamine derivatives, through the sialic acid pathway, might result in the expression of sialoglycans with altered hydrophobicity which in-turn could modulate their binding to endogenous lectins, including selectins. Herein, we show that treatment of HL-60 (human acute myeloid leukemia) cells with peracetyl N-cyclobutanoyl-D-mannosamine (Ac4ManNCb), at 50 microM for 48 h, resulted in a robust three to four fold increase in the binding of anti-sLeX (CSLEX1) antibody and enhanced cell adhesion to E-selectin coated surfaces; while the corresponding straight-chain analogue, peracetyl N-pentanoyl-D-mannosamine (Ac4ManNPent), and peracetyl N-cyclopropanoyl-D-mannosamine (Ac4ManNCp) both resulted in 2.0-2.5fold increase compared to controls. The ability to enhance sLeX expression using small molecules has the potential to provide novel opportunities to address challenges in the treatment of immune deficiency disorders.


Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1648
Author(s):  
Minoru Sasaki ◽  
Yu Shimoyama ◽  
Yoshitoyo Kodama ◽  
Taichi Ishikawa

Porphyromonas gingivalis is the most common microorganism associated with adult periodontal disease, causing inflammation around the subgingival lesion. In this study, we investigated tryptophanyl tRNA synthase (WRS) production by THP-1 cells infected with P. gingivalis. Cytokine production, leukocyte adhesion molecules, and low-density lipoprotein receptor (LDLR) expressions in cultured cells were examined. WRS was detected in THP-1 cell culture supernatants stimulated with P. gingivalis from 1 to 24 h, and apparent production was observed after 4 h. No change in WRS mRNA expression was observed from 1 to 6 h in THP-1 cells, whereas its expression was significantly increased 12 h after stimulation with P. gingivalis. Lactate dehydrogenase (LDH) activity was observed from 4 to 24 h. The TNF-α, IL-6, IL-8, and CXCL2 levels of THP-1 cells were upregulated after treatment with recombinant WRS (rWRS) and were significantly reduced when THP-1 cells were treated with C29. The MCP-1, ICAM-1, and VCAM-1 levels in human umbilical vein endothelial cells were upregulated following treatment with rWRS, and TAK242 suppressed these effects. Additionally, unmodified LDLR, macrophage scavenger receptor A, and lectin-like oxidized LDLRs were upregulated in THP-1 cells treated with rWRS. These results suggest that WRS from macrophages infected with P. gingivalis is associated with atherosclerosis.


Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7480
Author(s):  
Gabriele Serreli ◽  
Melanie Le Sayec ◽  
Camilla Diotallevi ◽  
Alice Teissier ◽  
Monica Deiana ◽  
...  

Nitric oxide (NO) is an important signaling molecule involved in many pathophysiological processes. NO mediates vasodilation and blood flow in the arteries, and its action contributes to maintaining vascular homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Dietary antioxidants and their metabolites have been found to be directly and/or indirectly involved in the modulation of the intracellular signals that lead to the production of NO. The purpose of this study was to investigate the contribution of conjugated metabolites of hydroxytyrosol (HT) and tyrosol (TYR) to the release of NO at the vascular level, and the related mechanism of action, in comparison to their parental forms. Experiments were performed in human aortic endothelial cells (HAEC) to evaluate the superoxide production, the release of NO and production of cyclic guanosine monophosphate (cGMP), the activation of serine/threonine-protein kinase 1 (Akt1), and the activation state of endothelial nitric oxide synthase (eNOS). It was observed that the tested phenolic compounds enhanced NO and cGMP concentration, inhibiting its depletion caused by superoxide overproduction. Moreover, some of them enhanced the activation of Akt (TYR, HT metabolites) and eNOS (HT, HVA, TYR-S, HT-3S). Overall, the obtained data showed that these compounds promote NO production and availability, suggesting that HT and TYR conjugated metabolites may contribute to the effects of parental extra virgin olive oil (EVOO) phenolics in the prevention of cardiovascular diseases.


Author(s):  
Herintha Coeto Neitzke-Abreu ◽  
Rhuan Carlos Souza Caetano ◽  
Kárin Rosi Reinhold-Castro ◽  
Manoel Sebastião da Costa Lima-Junior ◽  
Wagner José Tenório dos Santos ◽  
...  

Background: We aimed to determine the cellular recruitment (leukocyte rolling and adhesion) by which the Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis, and L. (Leishmania) major species in the mesenteric microcirculation of BALB/c mice. Methods: Five experimental groups were considered: group 1 (L. braziliensis); group 2 (L. amazonensis); group 3 (L. major); group 4 (control group with PBS); group 5 (negative control group), analyzed 3, 6, 12, and 24 h after parasite inoculation. Results: Infections by the different Leishmania species caused an increase in the number of rolling leukocytes: L. braziliensis a peak at 6 h; L. amazonensis and L. major a peak at 3 h. The Leishmania infections induced leukocyte adhesion: L. major and L. amazonensis showed an increase after 3 and 6 h, respectively. Conclusion: The kinetics of cellular recruitment in Leishmania infections, leading to infection susceptibility or resistance, indicates that distinct mechanisms regulate the initial response to Leishmania infection and determine its course.


2021 ◽  
Author(s):  
Edyta Skurska ◽  
Bożena Szulc ◽  
Dorota Maszczak-Seneczko ◽  
Maciej Wiktor ◽  
Wojciech Wiertelak ◽  
...  

Abstract Mutations in the SLC35C1 gene, encoding the Golgi GDP-fucose transporter, cause leukocyte adhesion deficiency II (LADII). Fucosylation improvement in LADII patients treated with fucose suggests the existence of an SLC35C1-independent route of GDP-fucose transport, which still remains a mystery. Here, we developed and characterized a human cell-based model deficient in the SLC35C1 activity. The knockout cells displayed low but detectable levels of fucosylation. Strikingly, the fucosylation defect was almost completely reversed upon treatment with millimolar concentrations of fucose. Even if fucose was supplemented at nanomolar concentrations, it was still incorporated into glycans by the knockout cells. We also found that the SLC35C1-independent transport preferred the salvage pathway over the de novo pathway as a source of GDP-fucose. Our results imply that the Golgi systems of GDP-fucose transport discriminate between the substrate pools obtained from different metabolic pathways, which suggests a functional connection between nucleotide sugar transporters and nucleotide sugar synthetases.


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