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Cells
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New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation
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New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 5115

Special Issue Editor

Dr. Shampa Chatterjee

E-Mail Website
Guest Editor
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Interests: pulmonary endothelial signaling; reactive oxygen species; NLRP3 inflammasome; inflammation–immune signals; danger signals; ischemia-reperfusion injury; graft rejection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The endothelium, a monolayer of endothelial cells, has been well-established to control blood fluidity, platelet aggregation, and vascular tone. However, its other characteristics, such as its ability to shift phenotype in a changing environment and orchestrate inflammation and immune signaling, are gradually coming to the fore. Various recent events, including the COVID-19 pandemic, have drawn unprecedented attention to these characteristics that eventually drive morbidity and mortality. Indeed, endothelial signals that drive inflammation and innate and adaptive immune functions are an evolving paradigm that have not been well understood thus far. It seems that endothelial cells are activated directly via oxidants or the engagement of pattern recognition receptors or indirectly via leukocyte trafficking (from blood) into interstitial tissue. Under physiological conditions, the endothelium balances the release of oxidants as well as of vasodilating or vasoconstricting factors and inflammation signals to maintain vascular tone, function, and permeability. However, during states of inflammation and injury, the endothelial surface becomes adherent and pro-coagulant; furthermore, it also transforms into a “recognition and response” layer that is integral to innate and adaptive immune system activation. In the long term, these activated pathways can lead to chronic diseased states that can often affect patient survival. The indiscriminate blockade of these pathways is not an option, as these are important components of immune protection. Therefore, we need a detailed understanding of the onset and amplification of endothelial signals so that we can employ interventions that are designed to only regulate certain elements of these pathways and to protect endothelial function while maintaining immune regulation. 

This Special Issue on “New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation” will showcase work by leading research groups that provide mechanistic information and that will thus shed light on the complex roles of vascular endothelium in pathophysiology. I invite and welcome authors to submit original research, review, mini-review, perspective, and opinion articles focusing on, but not limited to, the following subtopics:

•    Redox signaling in endothelial cells (EC); 
•    Insights on EC differentiation and transformation; 
•    EC in innate and adaptive immunity;
•    ECs in pathological immune responses;
•    The endothelium as a target for pathogens; 
•    EC in vascular homeostasis and its disruption; 
•    Vasodilation–vasoconstriction, angiogenesis, and vasculogenesis.
•    Therapeutic approaches to target ECs in inflammation–immune related diseases.

Dr. Shampa Chatterjee
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • vascular endothelium
  • inflammation
  • innate immunity
  • adaptive immunity
  • reactive oxygen species
  • pattern recognition receptors
  • immunomodulation

Published Papers (4 papers)

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Research

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26 pages, 4407 KiB  
Article
Moderate Elevation of Homocysteine Induces Endothelial Dysfunction through Adaptive UPR Activation and Metabolic Rewiring
by Barun Chatterjee, Fabeha Fatima, Surabhi Seth and Soumya Sinha Roy
Cells 2024, 13(3), 214; https://doi.org/10.3390/cells13030214 - 24 Jan 2024
Viewed by 1247
Abstract
Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with mutations in the methionine-cysteine metabolic cycle as well as with nutritional deficiency and aging. The previous literature suggests that HHcy is a strong risk factor [...] Read more.
Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with mutations in the methionine-cysteine metabolic cycle as well as with nutritional deficiency and aging. The previous literature suggests that HHcy is a strong risk factor for cardiovascular diseases. Severe HHcy is well-established to correlate with vascular pathologies primarily via endothelial cell death. Though moderate HHcy is more prevalent and associated with an increased risk of cardiovascular abnormalities in later part of life, its precise role in endothelial physiology is largely unknown. In this study, we report that moderate elevation of Hcy causes endothelial dysfunction through impairment of their migration and proliferation. We established that unlike severe elevation of Hcy, moderate HHcy is not associated with suppression of endothelial VEGF/VEGFR transcripts and ROS induction. We further showed that moderate HHcy induces a sub-lethal ER stress that causes defective endothelial migration through abnormal actin cytoskeletal remodeling. We also found that sub-lethal increase in Hcy causes endothelial proliferation defect by suppressing mitochondrial respiration and concomitantly increases glycolysis to compensate the consequential ATP loss and maintain overall energy homeostasis. Finally, analyzing a previously published microarray dataset, we confirmed that these hallmarks of moderate HHcy are conserved in adult endothelial cells as well. Thus, we identified adaptive UPR and metabolic rewiring as two key mechanistic signatures in moderate HHcy-associated endothelial dysfunction. As HHcy is clinically associated with enhanced vascular inflammation and hypercoagulability, identifying these mechanistic pathways may serve as future targets to regulate endothelial function and health. Full article
(This article belongs to the Special Issue New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation)
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26 pages, 6500 KiB  
Article
The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury
by Zahra Mahamed, Mohammad Shadab, Rauf Ahmad Najar, Michelle Warren Millar, Jashandeep Bal, Traci Pressley and Fabeha Fazal
Cells 2024, 13(1), 5; https://doi.org/10.3390/cells13010005 - 19 Dec 2023
Viewed by 1180
Abstract
Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been [...] Read more.
Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis. Full article
(This article belongs to the Special Issue New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation)
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31 pages, 8091 KiB  
Article
Chronic Kidney Disease Transdifferentiates Veins into a Specialized Immune–Endocrine Organ with Increased MYCN-AP1 Signaling
by Fatma Saaoud, Laisel Martinez, Yifan Lu, Keman Xu, Ying Shao, Jia L Zhuo, Avrum Gillespie, Hong Wang, Marwan Tabbara, Alghidak Salama, Xiaofeng Yang and Roberto I. Vazquez-Padron
Cells 2023, 12(11), 1482; https://doi.org/10.3390/cells12111482 - 26 May 2023
Cited by 1 | Viewed by 1541
Abstract
Most patients with end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) choose hemodialysis as their treatment of choice. Thus, upper-extremity veins provide a functioning arteriovenous access to reduce dependence on central venous catheters. However, it is unknown whether CKD reprograms the [...] Read more.
Most patients with end-stage renal disease (ESRD) and advanced chronic kidney disease (CKD) choose hemodialysis as their treatment of choice. Thus, upper-extremity veins provide a functioning arteriovenous access to reduce dependence on central venous catheters. However, it is unknown whether CKD reprograms the transcriptome of veins and primes them for arteriovenous fistula (AVF) failure. To examine this, we performed transcriptomic analyses of bulk RNA sequencing data of veins isolated from 48 CKD patients and 20 non-CKD controls and made the following findings: (1) CKD converts veins into immune organs by upregulating 13 cytokine and chemokine genes, and over 50 canonical and noncanonical secretome genes; (2) CKD increases innate immune responses by upregulating 12 innate immune response genes and 18 cell membrane protein genes for increased intercellular communication, such as CX3CR1 chemokine signaling; (3) CKD upregulates five endoplasmic reticulum protein-coding genes and three mitochondrial genes, impairing mitochondrial bioenergetics and inducing immunometabolic reprogramming; (4) CKD reprograms fibrogenic processes in veins by upregulating 20 fibroblast genes and 6 fibrogenic factors, priming the vein for AVF failure; (5) CKD reprograms numerous cell death and survival programs; (6) CKD reprograms protein kinase signal transduction pathways and upregulates SRPK3 and CHKB; and (7) CKD reprograms vein transcriptomes and upregulates MYCN, AP1, and 11 other transcription factors for embryonic organ development, positive regulation of developmental growth, and muscle structure development in veins. These results provide novel insights on the roles of veins as immune endocrine organs and the effect of CKD in upregulating secretomes and driving immune and vascular cell differentiation. Full article
(This article belongs to the Special Issue New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation)
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Review

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19 pages, 362 KiB  
Review
HIV Infection, Antiretroviral Drugs, and the Vascular Endothelium
by Georgette D. Kanmogne
Cells 2024, 13(8), 672; https://doi.org/10.3390/cells13080672 - 12 Apr 2024
Viewed by 535
Abstract
Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome. Despite viral suppression with combination antiretroviral therapy (ART), people living with HIV (PLWH) are prone to [...] Read more.
Endothelial cell activation, injury, and dysfunction underlies the pathophysiology of vascular diseases and infections associated with vascular dysfunction, including human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome. Despite viral suppression with combination antiretroviral therapy (ART), people living with HIV (PLWH) are prone to many comorbidities, including neurological and neuropsychiatric complications, cardiovascular and metabolic diseases, premature aging, and malignancies. HIV and viral proteins can directly contribute to the development of these comorbidities. However, with the continued high prevalence of these comorbidities despite viral suppression, it is likely that ART or some antiretroviral (ARVs) drugs contribute to the development and persistence of comorbid diseases in PLWH. These comorbid diseases often involve vascular activation, injury, and dysfunction. The purpose of this manuscript is to review the current literature on ARVs and the vascular endothelium in PLWH, animal models, and in vitro studies. I also summarize evidence of an association or lack thereof between ARV drugs or drug classes and the protection or injury/dysfunction of the vascular endothelium and vascular diseases. Full article
(This article belongs to the Special Issue New Insights into Endothelial Signaling: Inflammation, Infection and Immune Modulation)
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