Upregulation Of Adhesion Molecules Research Articles

Endothelial cells: potential novel regulators of renal inflammation.

Substantial evidence has supported the role of endothelial cell (EC) activation and dysfunction in the development of hypertension, chronic kidney disease (CKD), and lupus nephritis (LN). In both humans and experimental models of hypertension, CKD, and LN, ECs become activated and release potent mediators of inflammation including cytokines, chemokines, and reactive oxygen species that cause EC dysfunction, tissue damage, and fibrosis. Factors that activate the endothelium include inflammatory cytokines, mechanical stretch, and pathological shear stress. These signals can activate the endothelium to promote upregulation of adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which promote leukocyte adhesion and migration to the activated endothelium. More importantly, it is now recognized that some of these signals may in turn promote endothelial antigen presentation through major histocompatibility complex II. In this review, we will consider in-depth mechanisms of endothelial activation and the novel mechanism of endothelial antigen presentation. Moreover, we will discuss these proinflammatory events in renal pathologies and consider possible new therapeutic approaches to limit the untoward effects of endothelial inflammation in hypertension, CKD, and LN.

Interleukin-1 Receptor-Like 2: One Receptor, Three Agonists, and Many Implications.

The interleukin (IL)-1 superfamily of cytokines comprises 11 pro- and anti-inflammatory cytokines, which play essential roles during the immune response. Several pathogenic pathways are initiated by IL-1RL2 (interleukin 1 receptor-like 2) signaling, also known as IL-36R, in the skin, lungs, and gut. IL-36 cytokines promote the secretion of proinflammatory cytokines and chemokines, upregulation of antimicrobial peptides, proliferation mediators, and adhesion molecules on endothelial cells. In addition, the IL-36-IL-1RL2 axis has an essential role against viral infections, including a potential role in COVID-19 pathology. The evidence presented in this review highlights the importance of the axis IL-36-IL-1RL2 in the development of several inflammation-related diseases and the healing process. It suggests that IL-1RL2 ligands have specific roles depending on the tissue or cell source. However, there is still much to discover about this cytokine family, their functions in other organs, and how they accomplish a dual effect in inflammation and healing.

Upregulation of Neural Cell Adhesion Molecule 1 and Excessive Migration of Purkinje Cells in Cerebellar Cortex.

Purkinje cells (PCs) are large GABAergic projection neurons of the cerebellar cortex, endowed with elaborate dendrites that receive a multitude of excitatory inputs. Being the only efferent neuron of the cerebellar cortex, PCs project to cerebellar nuclei and control behaviors ranging from movement to cognition and social interaction. Neural cell adhesion molecule 1 (NCAM1) is widely expressed in the embryonic and postnatal development of the brain and plays essential roles in neuronal migration, axon pathfinding and synapse assembly. However, despite its high expression levels in cerebellum, little is known to date regarding the role(s) of NCAM1 in PCs development. Among other aspects, elucidating how the expression of NCAM1 in PCs could impact their postnatal migration would be a significant achievement. We analyzed the Acp2 mutant mouse (nax: naked and ataxia), which displays excessive PC migration into the molecular layer, and investigated how the excessive migration of PCs along Bergmann glia could correlate to NCAM1 expression pattern in early postnatal days. Our Western blot and RT-qPCR analysis of the whole cerebellum show that the protein and mRNA of NCAM1 in wild type are not different during PC dispersal from the cluster stage to monolayer formation. However, RT-qPCR analysis from FACS-based isolated PCs shows that Ncam1 is significantly upregulated when PCs fail to align and instead overmigrate into the molecular layer. Our results suggest two alternative interpretations: (1) NCAM1 promotes excessive PC migration along Bergmann glia, or (2) NCAM1 upregulation is an attempt to prevent PCs from invading the molecular layer. If the latter scenario proves true, NCAM1 may play a key role in PC monolayer formation.

Traditional Patchouli essential oil modulates the host’s immune responses and gut microbiota and exhibits potent anti-cancer effects in ApcMin /+ mice

Patchouli Essential Oil (PEO) has been used as a scent for various healing purposes since the ancient Egyptian period. The primary source of the oil is Pogostemon cablin (PC), a medicinal plant for treating gastrointestinal symptoms. However, the pharmacological function has not been addressed. Here, we report the cancer prevention and gut microbiota (GM) modulating property of PEO and its derivatives patchouli alcohol (PA) and pogostone (PO) in the ApcMin /+ colorectal cancer mice model. We found that PEO, PA, and PO significantly reduced the tumor burden. At the same time, it strengthened the epithelial barrier, evidenced by substantially increasing the number of the goblet and Paneth cells and upregulation of tight junction and adhesion molecules. In addition, PEO, PA, and PO shifted M1 to M2 macrophage phenotypes and remodeled the inflammatory milieu of ApcMin /+ mice. We also found suppression of CD4+CD25+ and stimulation CD4+ CD8+ cells in the spleen, blood, mesenteric lymph nodes (MLNs), and Peyer’s patches (PPs) of the treated mice. The composition of the gut microbiome of the drug-treated mice was distinct from the control mice. The drugs stimulated the short-chain fatty acids (SCFAs)-producers and the key SCFA-sensing receptors (GPR41, GPR43, and GPR109a). The activation of SCFAs/GPSs also triggered the alterations of PPAR-γ, PYY, and HSDCs signaling mediators in the treated mice. Our work showed that PEO and its derivatives exert potent anti-cancer effects by modulating gut microbiota and improving the intestinal microenvironment of the ApcMmin /+ mice.

Vascular inflammation in the central nervous system.

Vascular inflammation in the central nervous system.

Static Adhesion Assay for Human Peripheral Blood Mononuclear Cells.

Blood endothelial cells (ECs) constitute the primary physical barrier to be crossed by circulating leukocytes, once attracted to a site of ongoing inflammation/infection. Upon a pro-inflammatory stimulus, such as tumor necrosis factor (TNF), ECs upregulate adhesion molecule expression to favor the adhesion and, subsequently, the transendothelial migration of the attracted lymphocytes. To address the ability of a cell to transmigrate through a monolayer of ECs, the classical transmigration assay is usually performed (Muller and Luscinskas, 2008). In the present protocol, adapted from Safuan et al. (2012), we describe an in vitro assay for assessing the functionality of the second step of the transendothelial migration, i.e., the firm adhesion of peripheral blood mononuclear cells (PBMCs) to ECs, under static conditions. By pre-incubating primary human umbilical cord ECs (HUVECs) with either innate lymphoid cell progenitors (ILCPs) or TNF, we were able to upregulate adhesion molecules on the EC surface. Then, by adding total PBMCs, we were able to both quantitatively and qualitatively analyze the cellular subtype and number of PBMCs that adhered to the pre-treated ECs. The important advantage of this technique is the possibility to perform functional studies on ECs biology since, differently from transwell-based strategies, it allows a good recovery of ECs at the end of the assay. Overall, this assay enables to interrogate how/if different stimulations/cell types can influence EC ability to retain PBMCs in vitro, under static conditions. Graphic abstract: The workflow of the Static Adhesion Assay.

Coagulation Disorders and Thrombosis in COVID-19 Patients and a Possible Mechanism Involving Endothelial Cells: A Review.

Coronavirus disease 2019 (COVID-19) is still an ongoing pandemic worldwide. COVID-19 is an age-related disease with a higher risk of organ dysfunction and mortality in older adults. Coagulation disorders and thrombosis are important pathophysiological changes in COVID-19 infection. Up to 95% of COVID-19 patients have coagulation disorders characterized by an elevated D-dimer, a prolonged prothrombin time, a low platelet count and other laboratory abnormalities. Thrombosis is found in critical cases with an increased risk of death. Endothelial cells are prone to be affected by the novel SARS-CoV-2 and express angiotensin-converting enzyme 2. The evidence, such as the presence of the virus, has been identified, leading to the inflammation and dysfunction. Endothelial cell activation and dysfunction play a pivotal role in the hypercoagulation status in COVID-19 patients. In addition to the direct exposure of subendothelial tissue to blood, Weibel-Palade bodies within the endothelium containing coagulants can be released into the circulation. Endothelial nitric oxide synthase may be impaired, thus facilitating platelet adhesion. Moreover, anti-β2-glycoprotein I antibodies may also contribute to the coagulopathy in COVID-19 by inducing the upregulation of proinflammatory mediators and adhesion molecules. To conclude, coagulation disorders and thrombosis are vital and predict a poor outcome in COVID-19 patients, especially in severe cases. Endothelial cell activation and dysfunction may play an important role in causing clot formation. More basic and clinical research is warranted to further our understanding of the role of coagulopathy and their possible mechanism in COVID-19 patients.

VCAM1, HMOX1 and NOS3 differential endothelial expression may impact sickle cell anemia vasculopathy

Endothelial dysfunction plays a major role in sickle cell anemia (SCA) systemic vasculopathy, with upregulation of adhesion molecules (e.g., VCAM-1), decreased nitric oxide bioavailability, and oxidative stress. We aimed to assess the modulation role of pro-inflammatory and pro-oxidative stimuli on endothelial VCAM1, NOS3, and HMOX1 expression. We also evaluated the effect of the main SCA therapeutic agent, hydroxyurea, on that modulation.Our results showed that two VCAM1 promoter haplotypes, we previously associated with pediatric cerebral vasculopathy and severe hemolysis in SCA, increased promoter activity in TNF-α-stimulated transfected EA.hy926 and HBEC cell lines, consistent with a higher VCAM1 expression in macro and microvascular settings. In non-transfected cells, we also observed TNF-α-induced VCAM1 overexpression as well as heme-induced overexpression of HMOX1 in both cell models. Heme did not affect VCAM1 nor NOS3 expression and the latter was also not affected by TNF-α stimulus. Hydroxyurea treatment lowered TNF-induced VCAM1 and NOS3 expression but did not affect heme-induced HMOX1 expression.These data further indicate that VCAM1 haplotypes we studied lead to higher VCAM1 expression affecting not only cerebral but also systemic vasculopathy risk. The differential endothelial expression of VCAM1, NOS3, and HMOX1 also confirms their genetic modulation role in SCA systemic vasculopathy.

Gut dysbiosis and gut-derived inflammation contribute to endothelial dysfunction in Alzheimer's disease: An in-vivo cross-sectional study.

Although recent data support an association between certain bacterial strains and Alzheimer's Disease (AD), it is not clear how these alterations contribute to different aspects of the disease. Increasing evidences also from our group (Cattaneo, AAIC 2020), suggest that endothelial dysfunction, reflected by the upregulation of cell adhesion molecules (CAMs), might have a role in AD pathology development and might be affected by inflammatory mediators. This study aimed at evaluating the gut microbiota (GMB) profile and its association with CAMs and local and systemic inflammation in AD patients. Sixty-six older persons without cognitive performance (HC) and 68 AD patients were recruited and stool and blood samples were collected. Bacterial composition of fecal samples was inferred using 16S sequencing, analyzed with QIIME 2 (Quantitative Insights into Microbial Ecology, https://qiime2.org/). Inflammatory mediators were quantified in the blood using the mesoscale platform (for cytokines) and in the stools using ELISA (for calprotectin), CAMs by FACS. Compared to HC, AD patients showed i) lower abundance of genera known to have anti-inflammatory, neuroprotective or other beneficial effects on the epithelial barrier (as Akkermansia, Roseburia and Fusicatenibacter) as well as higher abundance in pro-inflammatory genera (as Desulfovibrio) (Lefse, p< 0.039); ii) higher levels of the proinflammatory cytokine IL8 (p= 0.044) in the blood and calprotectin in the stools (p= 0.012); iii) higher level of several adhesion molecules (NCAM, PECAM-1, P-, L-, E-Selectin; p< 0.024) in the blood. Low abundance of the beneficial genera as well as high abundance of the proinflammatory genera were associated with elevated levels of fecal calprotectin and blood CAMs (0.19<|rho|<0.30, p<.048). Finally, high calprotectin levels were associated with elevated CAMs expression (0.22<|rho|<0.32, p<.017). These findings confirm our previous results showing that gut dysbiosis was associated with endothelial dysfunction. In addition, we showed that gut derived inflammation, linked to both altered bacteria abundance and CAMs upregulation, might contribute to AD.

Hepatocellular carcinoma cell line-microenvironment induced cancer-associated phenotype, genotype and functionality in mesenchymal stem cells

Mesenchymal stromal cells (MSCs) have shown promise in liver cancer treatment. However, when MSCs are recruited to hepatic site of injury, they acquire cancerous promoting phenotype. Aims: To assess the influence of Hepatocellular carcinoma (HCC) microenvironment on human adipose MSCs (hA-MSCs) and predict hA-MSCs intracellular miRNAs role. Materials and Methods: After indirect co-culturing with Huh-7 cells, hA-MSCs were characterized via cell cycle profile, proliferation and migration potentials by MTT and scratch assays respectively. Functional enrichment analysis of deregulated proteins and miRNA targets was also analyzed. Key findings: Co-cultured hA-MSCs could acquire a cancer-associated phenotype as shown by upregulation of CAF, cancer markers, and downregulation of differentiation markers. Migration of these cancer-associated cells was increased concomitantly with upregulation of adhesion molecules, but not epithelial to mesenchymal transition markers. Co-cultured cells showed increased proliferation confirmed by downregulation in cell percentage in G0/G1, G2/M and upregulation in S phases of cell cycle. Upregulation of miR-17-5p and 615-5p in co-cultured hA-MSCs was also observed. Functional enrichment analysis of dysregulated proteins in co-cultured hA-MSCs, including our selected miRNAs targets, showed their involvement in development of cancer-associated characteristics. Significance: This study suggests an interaction between tumor cells and surrounding stromal components to generate cancer associated phenotype of some CAF-like characteristics, known to favor cancer progression. This sheds the light on the use of hA-MSCs in HCC therapy. hA-MSCs modulation may be partially achieved via dysregulation of intracellular miR17-5P and 615-5p expression, suggesting an important role for miRNAs in HCC pathogenesis, and as a possible therapeutic candidate.

Oligodendrocytes regulate the adhesion molecule ICAM-1 in neuroinflammation.

Recently, oligodendrocytes (Ol) have been attributed potential immunomodulatory effects. Yet, the exact mode of interaction with pathogenic CNS infiltrating lymphocytes remains unclear. Here, we attempt to dissect mechanisms of Ol modulation during neuroinflammation and characterize the interaction of Ol with pathogenic T cells. RNA expression analysis revealed an upregulation of immune-modulatory genes and adhesion molecules (AMs), ICAM-1 and VCAM-1, in Ol when isolated from mice undergoing experimental autoimmune encephalomyelitis (EAE). To explore whether AMs are involved in the interaction of Ol with infiltrating T cells, we performed co-culture studies on mature Ol and Th1 cells. Live cell imaging analysis showed direct interaction between both cell types. Eighty percentage of Th1 cells created contacts with Ol that lasted longer than 15 min, which may be regarded as physiologically relevant. Exposure of Ol to Th1 cells or their supernatant resulted in a significant extension of Ol processes, and upregulation of AMs as well as other immunomodulatory genes. Our observations indicate that blocking of oligodendroglial ICAM-1 can reduce the number of Th1 cells initially contacting the Ol. These results suggest that AMs may play a role in the interaction between Ol and Th1 cells. We identified Ol interacting with CD4+ cells in vivo in spinal cord tissue of EAE diseased mice indicating that our in vitro findings are of interest to further scientific research in this field. Further characterization and understanding of Ol interaction with infiltrating cells may lead to new therapeutic strategies enhancing Ol protection and remyelination potential. Oligodendrocytes regulate immune modulatory genes and adhesion molecules during autoimmune neuroinflammation Oligodendrocytes interact with Th1 cells in vitro in a physiologically relevant manner Adhesion molecules may be involved in Ol-Th1 cell interaction.

Thin films of functionalized carbon nanotubes support long-term maintenance and cardio-neuronal differentiation of canine induced pluripotent stem cells

Induced pluripotent stem cells (iPSCs) are a promising cell source for regenerative medicine. However, their feeder-free maintenance in undifferentiated states remains challenging. In recent past extensive studies have been directed using pristine or functionalized carbon nanotube in tissue engineering. Here we proposed thin films of functionalized carbon nanotubes (OH-single-walled CNTs [SWCNTs] and OH-multiwalled CNTs [MWCNTs]), as alternatives for the feeder-free in vitro culture of canine iPSCs (ciPSCs), considered as the cellular model. The ciPSC colonies could maintain their dome-shaped compactness and other characteristics when propagated on CNT films. Concomitantly, high cell viability and upregulation of pluripotency-associated genes and cell adhesion molecules were observed, further supported by molecular docking. Moreover, CNTs did not have profound toxic effects compared to feeder cultures as evident by cytocompatibility studies. Further, cardiac and neuronal differentiation of ciPSCs was induced on these films to determine their influence on the differentiation process. The cells retained differentiation potential and the nanotopographical features of the substrates provided positive cues to enhance differentiation to both lineages as evident by immunocytochemical staining and marker gene expression. Overall, OH-SWCNT provided better cues, maintained pluripotency, and induced the differentiation of ciPSCs. These results indicate that OH-functionalized CNT films could be used as alternatives for the feeder-free maintenance of ciPSCs towards prospective utilization in regenerative medicine.

Brain Immune Interactions-Novel Emerging Options to Treat Acute Ischemic Brain Injury.

Ischemic stroke is still among the leading causes of mortality and morbidity worldwide. Despite intensive advancements in medical sciences, the clinical options to treat ischemic stroke are limited to thrombectomy and thrombolysis using tissue plasminogen activator within a narrow time window after stroke. Current state of the art knowledge reveals the critical role of local and systemic inflammation after stroke that can be triggered by interactions taking place at the brain and immune system interface. Here, we discuss different cellular and molecular mechanisms through which brain–immune interactions can take place. Moreover, we discuss the evidence how the brain influence immune system through the release of brain derived antigens, damage-associated molecular patterns (DAMPs), cytokines, chemokines, upregulated adhesion molecules, through infiltration, activation and polarization of immune cells in the CNS. Furthermore, the emerging concept of stemness-induced cellular immunity in the context of neurodevelopment and brain disease, focusing on ischemic implications, is discussed. Finally, we discuss current evidence on brain–immune system interaction through the autonomic nervous system after ischemic stroke. All of these mechanisms represent potential pharmacological targets and promising future research directions for clinically relevant discoveries.

Metformin inhibits cholesterol‑induced adhesion molecule expression via activating the AMPK signaling pathway in vascular smooth muscle cells.

Recruitment of lymphocytes to the vascular wall contributes to the pathogenesis of atherosclerosis (AS). The expression of cellular adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, serves a critical role in mediating lymphocyte adhesion to the vascular wall. Cholesterol loading induces the expression of adhesion molecules in vascular smooth muscle cells (VSMCs), but the underlying mechanism is not completely understood. The present study aimed to investigate the mechanism underlying the effects of cholesterol on adhesion molecule expression, and whether metformin protected VSMCs against cholesterol-induced functional alterations. Human VSMCs were loaded with cholesterol and different concentrations of metformin. The expression levels of adhesion molecules were assessed via reverse transcription-quantitative PCR and western blotting. Reactive oxygen species (ROS) accumulation and levels were quantified via fluorescence assays and spectrophotometry, respectively. AMP-activated protein kinase (AMPK), p38 MAPK and NF-κB signaling pathway-related protein expression levels were evaluated via western blotting. Compared with the control group, cholesterol loading significantly upregulated adhesion molecule expression levels on VSMCs by increasing intracellular ROS levels and activating the p38 MAPK and NF-κB signaling pathways. Metformin decreased cholesterol-induced VSMC damage by activating the AMPK signaling pathway, and suppressing p38 MAPK and NF-κB signaling. The present study indicated the therapeutic potential of metformin for VSMC protection, reduction of monocyte adhesion, and ultimately, the prevention and treatment of AS.

Early Endothelial Activation in a Mouse Model of Graft vs Host Disease Following Chemotherapy.

Allogenic hematopoietic stem cell transplant (allo-HSCT) can lead to sinusoidal obstruction syndrome (SOS) and graft-versus-host disease (GvHD) in some individuals. GvHD is characterised by an immune triggered response that arises due to donor T cells recognizing the recipient tissue as “foreign”. SOS results in impaired liver function due to microvascular thrombosis and consequent obstruction of liver sinusoids. Endothelial damage occurs following chemotherapy and allo-HSCT and is strongly associated with GvHD onset as well as hepatic SOS. Animal models of GvHD are rarely clinically relevant, and endothelial dysfunction remains uncharacterised. Here we established and characterised a clinically relevant model of GvHD wherein Balb/C mice were subjected to myeloablative chemotherapy followed by transplantation of bone marrow (BM) cells± splenic T-cells from C57Bl6 mice, resulting in a mismatch of major histocompatibility complexes (MHC). Onset of disease indicated by weight loss and apoptosis in the liver and intestine was discovered at day 6 post-transplant in mice receiving BM+T-cells, with established GvHD detectable by histology of the liver within 3 weeks. Together with significant increases in pro-inflammatory cytokine gene expression in the liver and intestine, histopathological signs of GvHD and a significant increase in CD4+ and CD8+ effector and memory T-cells were seen. Endothelial activation including upregulation of vascular cell adhesion molecule (VCAM)- 1 and downregulation of endothelial nitric oxide synthase (eNOS) as well as thrombosis in the liver indicated concomitant hepatic SOS. Our findings confirm that endothelial activation is an early sign of acute GvHD and SOS in a clinically relevant mouse model of GvHD based on myeloablative chemotherapy. Preventing endothelial activation may be a viable therapeutic strategy to prevent GvHD.

KLF7 Promotes Gastric Carcinogenesis Through Regulation of ANTXR1.

PurposeElucidating the mechanism of gastric cancer progression is of great importance for the discovery of new therapy targets against gastric cancer. In this study, we investigated the function of Kruppel-like factor 7 (KLF7) in gastric cancer.MethodsqPCR and Western blot were performed to determine the expression of ANTXR1 after KLF7 inhibition. CCK-8, colony formation, apoptosis analysis, cell cycle analysis and transwell assay were performed to determine KLF7 functions in cellular proliferation, migration, apoptosis and cell cycle. Tumour xenograft experiments were performed to examine cell growth in vivo.ResultsThe results showed that KLF7 was upregulated in gastric cancer. The proliferation and migration of gastric cancer cells were suppressed by depletion of KLF7. In vivo tumour progression was also attenuated following the downregulation of KLF7. Meanwhile, overexpression of KLF7 promoted the proliferation and migration of gastric cancer cells. The results of the mechanistic analysis showed that KLF7 promoted gastric carcinogenesis via upregulation of ANTXR cell adhesion molecule 1 (ANTXR1).ConclusionTherefore, this study may provide a theoretical foundation for further clinical therapy of gastric cancer.

Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders.

Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), and PAI-1 (p < 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, p = 0.003) and AQ levels (r = 0.512, p = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed.

The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19.

Atherosclerosis is considered a disease caused by a chronic inflammation, associated with endothelial dysfunction, and several mediators of inflammation are up-regulated in subjects with atherosclerotic disease. Healthy, intact endothelium exhibits an antithrombotic, protective surface between the vascular lumen and vascular smooth muscle cells in the vessel wall. Oxidative stress is an imbalance between anti- and prooxidants, with a subsequent increase of reactive oxygen species, leading to tissue damage. The renin-angiotensin-aldosterone system is of vital importance in the pathobiology of vascular disease. Convincing data indicate that angiotensin II accelerates hypertension and augments the production of reactive oxygen species. This leads to the generation of a proinflammatory phenotype in human endothelial and vascular smooth muscle cells by the up-regulation of adhesion molecules, chemokines and cytokines. In addition, angiotensin II also seems to increase thrombin generation, possibly via a direct impact on tissue factor. However, the mechanism of cross-talk between inflammation and haemostasis can also contribute to prothrombotic states in inflammatory environments. Thus, blocking of the renin-angiotensin-aldosterone system might be an approach to reduce both inflammatory and thrombotic complications in high-risk patients. During COVID-19, the renin-angiotensin-aldosterone system may be activated. The levels of angiotensin II could contribute to the ongoing inflammation, which might result in a cytokine storm, a complication that significantly impairs prognosis. At the outbreak of COVID-19 concerns were raised about the use of angiotensin converting enzyme inhibitors and angiotensin receptor blocker drugs in patients with COVID-19 and hypertension or other cardiovascular comorbidities. However, the present evidence is in favor of continuing to use of these drugs. Based on experimental evidence, blocking the renin-angiotensin-aldosterone system might even exert a potentially protective influence in the setting of COVID-19.

Interleukin-1β enhances cell adhesion in human endothelial cells via microRNA-1914–5p suppression

Atherosclerosis is a chronic inflammatory disease and the underlying cause of most cardiovascular diseases. Interleukin (IL)-1β facilitates early atherogenic lesion formation by increasing monocyte adhesion to endothelial cells via upregulation of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1). MicroRNAs (miRNAs) have been shown to be associated with inflammatory conditions in the vascular system. The expression of circulating miR-1914–5p is reportedly downregulated in patients with cardiovascular diseases. However, the role of miR-1914–5p downregulation in IL-1β–induced endothelial cell dysfunction and the effect of miR-1914–5p on lesion formation remain unclear. Therefore, we investigated whether miR-1914–5p is associated with monocyte adhesion in human endothelial cells. IL-1β decreased miR-1914–5p expression in EA.hy926 cells. In addition, miR-1914–5p depletion enhanced ICAM-1 expression and monocyte adhesion in EA.hy926 cells. Moreover, miR-1914–5p mimic suppressed monocyte adhesion and ICAM-1 expression induced by IL-1β in endothelial cells. These results suggest that suppression of miR-1914–5p expression by IL-1β may be an important regulator in mediating monocyte adhesion in endothelial cells. Further investigation of miR-1914–5p may lead to the development of novel therapeutic strategies for atherosclerosis.

Cerebral Pericytes and Endothelial Cells Communicate through Inflammasome-Dependent Signals.

By upregulation of cell adhesion molecules and secretion of proinflammatory cytokines, cells of the neurovascular unit, including pericytes and endothelial cells, actively participate in neuroinflammatory reactions. As previously shown, both cell types can activate inflammasomes, cerebral endothelial cells (CECs) through the canonical pathway, while pericytes only through the noncanonical pathway. Using complex in vitro models, we demonstrate here that the noncanonical inflammasome pathway can be induced in CECs as well, leading to a further increase in the secretion of active interleukin-1β over that observed in response to activation of the canonical pathway. In parallel, a more pronounced disruption of tight junctions takes place. We also show that CECs respond to inflammatory stimuli coming from both the apical/blood and the basolateral/brain directions. As a result, CECs can detect factors secreted by pericytes in which the noncanonical inflammasome pathway is activated and respond with inflammatory activation and impairment of the barrier properties. In addition, upon sensing inflammatory signals, CECs release inflammatory factors toward both the blood and the brain sides. Consequently, CECs activate pericytes by upregulating their expression of NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3), an inflammasome-forming pattern recognition receptor. In conclusion, cerebral pericytes and endothelial cells mutually activate each other in inflammation.