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1
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Tough RH, McLaren PJ. Chromosome 1 variants associated with decreased HIV set-point viral load correlate with PRKAB2 expression changes. Front Genet 2025; 16:1551171. [PMID: 40115816 PMCID: PMC11922826 DOI: 10.3389/fgene.2025.1551171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/20/2025] [Indexed: 03/23/2025] Open
Abstract
A previous study investigated a genomic region on chromosome 1 associated with reduced human immunodeficiency virus type 1 (HIV) set-point viral load, implicating CHD1L as a novel HIV inhibitory factor. However, given that regulatory variants can influence expression of multiple nearby genes, further work is necessary to determine the impact of genetic variants on other genes in the region. This study evaluates the potential for genetic regulation of PRKAB2, a gene located upstream of CHD1L and encoding the β2 regulatory subunit of the AMPK complex, and for downstream impacts on HIV pathogenesis. Using genotype and gene expression data from the Gene Expression Omnibus repository and Genotype-Tissue Expression database, we observed cell-type-specific correlations between CHD1L and PRKAB2 expression, with a strong positive association in whole blood and negative correlation in monocytes. Notably, we found that individuals with HIV set-point viral load associated variants exhibited significantly reduced PRKAB2 expression in imputed whole blood models and ex vivo monocytes. Functional analyses using PRKAB2 -/- induced pluripotent stem cells suggest that PRKAB2 loss-of-function may influence CHD1L expression, and genes regulating cytokine activity, growth factor signaling, and pluripotency pathways associated with HIV infection. These results suggest that gene expression changes driven by HIV set-point viral load associated variants in the chromosome 1 impact multiple genes and, by influencing expression of PRKAB2, may result in altered expression of critical immune signaling processes. These findings advance our understanding of the contribution of host genetics on HIV pathogenesis and identifies new targets for ex vivo functional studies.
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Affiliation(s)
- Riley H Tough
- Sexually Transmitted and Blood-Borne Infections Division, National Microbiology Laboratories, Public Health Agency of Canada, Winnipeg, MB, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
| | - Paul J McLaren
- Sexually Transmitted and Blood-Borne Infections Division, National Microbiology Laboratories, Public Health Agency of Canada, Winnipeg, MB, Canada
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
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2
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Belyaev IB, Griaznova OY, Yaremenko AV, Deyev SM, Zelepukin IV. Beyond the EPR effect: Intravital microscopy analysis of nanoparticle drug delivery to tumors. Adv Drug Deliv Rev 2025:115550. [PMID: 40021012 DOI: 10.1016/j.addr.2025.115550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/18/2025] [Accepted: 02/18/2025] [Indexed: 03/03/2025]
Abstract
Delivery of nanoparticles (NPs) to solid tumors has long relied on enhanced permeability and retention (EPR) effect, involving permeation of NPs through a leaky vasculature with prolonged retention by reduced lymphatic drainage in tumor. Recent research studies and clinical data challenge EPR concept, revealing alternative pathways and approaches of NP delivery. The area was significantly impacted by the implementation of intravital optical microscopy, unraveling delivery mechanisms at cellular level in vivo. This review presents analysis of the reasons for EPR heterogeneity in tumors and describes non-EPR based concepts for drug delivery, which can supplement the current paradigm. One of the approaches is targeting tumor endothelium by NPs with subsequent intravascular drug release and gradient-driven drug transport to tumor interstitium. Others exploit various immune cells for tumor infiltration and breaking endothelial barriers. Finally, we discuss the involvement of active transcytosis through endothelial cells in NP delivery. This review aims to inspire further understanding of the process of NP extravasation in tumors and provide insights for developing next-generation nanomedicines with improved delivery.
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Affiliation(s)
- Iaroslav B Belyaev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Eindhoven University of Technology, Eindhoven 5600 MB, the Netherlands
| | - Olga Yu Griaznova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | | | - Sergey M Deyev
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | - Ivan V Zelepukin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Department of Immunology, Genetics and Pathology, Uppsala University 75123 Uppsala, Sweden.
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3
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Jiang Y, Li W, Ma Y, Hou Y. Neuroinflammation-targeted magnetic resonance imaging nanoprobes for the early diagnosis of Alzheimer's disease. J Mater Chem B 2025; 13:1424-1436. [PMID: 39686760 DOI: 10.1039/d4tb02210f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Alzheimer's disease (AD) that is an important contributor to dementia, is a chronic and irreversible neurodegenerative disease, with high rates of disability and mortality. Recently, more and more therapeutic methods have been developed to delay the progression of AD, but it remains a great challenge to achieve the early diagnosis of AD. In this work, we developed a magnetic resonance imaging (MRI) nanoprobe (NP@angiopep-2/CD137) based on angiopep-2 peptide and CD137 antibody with a NaGdF4 nanoparticle as the core and realized neuroinflammation-targeted imaging on APP/PS1 model mice using a clinical 7.0 T MRI scanner. CD137 expression was upregulated in neuroglial cells and cerebral vascular endothelial cells in inflammatory state. In the APP/PS1 mouse model, after administration, the nanoprobe-enhanced images showed specific dot-like signals in the susceptibility-weighted imaging (SWI) sequence. In summary, we designed and synthesized NP@angiopep-2/CD137 nanoprobes using the activation-dependent expression of CD137, which were applied to the pathological assessment of AD based on the hypothesis of AD neuroinflammation, and provided a reliable idea for the early molecular imaging diagnosis of AD.
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Affiliation(s)
- Yanjiao Jiang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Wenyue Li
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Yuqiang Ma
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Yi Hou
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
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4
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Shen L, Tian Q, Ran Q, Gan Q, Hu Y, Du D, Qin Z, Duan X, Zhu X, Huang W. Z-Ligustilide: A Potential Therapeutic Agent for Atherosclerosis Complicating Cerebrovascular Disease. Biomolecules 2024; 14:1623. [PMID: 39766330 PMCID: PMC11726876 DOI: 10.3390/biom14121623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Atherosclerosis (AS) is one of the major catalysts of ischemic cerebrovascular disease, and the death and disease burden from AS and its cerebrovascular complications are increasing. Z-ligustilide (Z-LIG) is a key active ingredient in Angelica sinensis (Oliv.) Diels and Ligusticum chuanxiong Hort. In this paper, we first introduced LIG's physicochemical properties and pharmacokinetics. Then, we reviewed Z-LIG's intervention and therapeutic mechanisms on AS and its cerebrovascular complications. The mechanisms of Z-LIG intervention in AS include improving lipid metabolism, antioxidant and anti-inflammatory effects, protecting vascular endothelium, and inhibiting vascular endothelial fibrosis, pathological thickening, and plaque calcification. In ischemic cerebrovascular diseases complicated by AS, Z-LIG exerts practical neuroprotective effects in ischemic stroke (IS), transient ischemic attack (TIA), and vascular dementia (VaD) through anti-neuroinflammatory, anti-oxidation, anti-neuronal apoptosis, protection of the blood-brain barrier, promotion of mitochondrial division and angiogenesis, improvement of cholinergic activity, inhibition of astrocyte proliferation, and endoplasmic reticulum stress. This paper aims to provide a basis for subsequent studies of Z-LIG in the prevention and treatment of AS and its cerebrovascular complications and, thus, to promote the development of interventional drugs for AS.
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Affiliation(s)
- Longyu Shen
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Qianqian Tian
- Faculty of Social Sciences, The University of Hong Kong, Hong Kong 999077, China
| | - Qiqi Ran
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Qianrong Gan
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Yu Hu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Donglian Du
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Zehua Qin
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Xinyi Duan
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
| | - Xinyun Zhu
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China;
| | - Wei Huang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (L.S.); (Z.Q.)
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5
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Jin T, Gao H, Meng D, Luo M, Hu J. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages. Open Med (Wars) 2024; 19:20241072. [PMID: 39450006 PMCID: PMC11500533 DOI: 10.1515/med-2024-1072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/26/2024] Open
Abstract
Background Ischemic stroke associated with atherosclerosis is globally named atherothrombotic stroke. Presently, the underlying pathogenic genes promoting carotid atherosclerotic plaques transfer from a stable to unstable state remains elusive. This study aims to find the hub genes disturbing the stability of plaques and explore the primary cells affected by these hub genes. Methods The optimal hub genes from five datasets for unstable plaques were identified by overlapping genes derived from Boruta and LASSO algorithms. The hub genes' expression levels in stroke patients were confirmed through RT-qPCR. Visualization of the hub genes' expression across various cell clusters was achieved with the aid of the Seurat R package. Then, hub genes were overexpressed or knock-down by lentivirus and siRNA, respectively. The inflammatory factors in the culture medium were detected using an ELISA assay. Results Eight genes (APOD, ASXL1, COL4A5, HTR7, INF2, NSUN6, PDSS2, and RBBP7) were identified and confirmed by RT-qPCR. The prognostic model was built upon this eight-gene composite foundation, and the area under the curve was 0.98. Based on CIBERSORT findings, unstable plaques displayed a higher macrophage proportion compared to stable ones (P < 0.05). These eight genes also correlated with infiltrated immune cells, especially macrophages. Then, according to single-cell RNA-seq analysis, we found that the eight hub genes mainly expressed in macrophages. The cellular localization of two hub genes (NSUN6 and HTR7) with high distinguishability was confirmed, and gene set enrichment analysis also clarified the possible biological pathways regulated by them. The findings from the in vitro investigation revealed that TNF-α and IL-6 were reduced in macrophages with NSUN6 overexpression or HTR7 knockdown. Conclusion Eight hub genes, especially NSUN6 and HTR7, were found to promote the progression of plaques by regulating the immune responses of macrophages.
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Affiliation(s)
- Tingyu Jin
- Department of Neurology, Affiliated Hospital of Jiaxing University, The First Hospital of Jiaxing, Jiaxing, Zhejiang, China
| | - Han Gao
- Department of Neurology, Affiliated Hospital of Jiaxing University, The First Hospital of Jiaxing, Jiaxing, Zhejiang, China
| | - Danyang Meng
- Department of Neurology, Affiliated Hospital of Jiaxing University, The First Hospital of Jiaxing, Jiaxing, Zhejiang, China
| | - Man Luo
- Department of Neurology, Affiliated Hospital of Jiaxing University, The First Hospital of Jiaxing, Jiaxing, Zhejiang, China
| | - Jin Hu
- Department of Neurology, Affiliated Hospital of Jiaxing University, The First Hospital of Jiaxing, 1882 Zhonghuan South Road, Chengnan Street, Jiaxing, Zhejiang, China
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6
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Zhang M, Lotfollahzadeh S, Elzinad N, Yang X, Elsadawi M, Gower AC, Belghasem M, Shazly T, Kolachalama VB, Chitalia VC. Alleviating iatrogenic effects of paclitaxel via antiinflammatory treatment. Vasc Med 2024; 29:369-380. [PMID: 38623630 PMCID: PMC11365010 DOI: 10.1177/1358863x241231942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
BACKGROUND Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. METHODS We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. RESULTS Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. CONCLUSION Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.
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Affiliation(s)
- Mengwei Zhang
- Department of Medicine, Renal Section, Boston University School of Medicine, Boston, MA, USA
| | - Saran Lotfollahzadeh
- Department of Medicine, Renal Section, Boston University School of Medicine, Boston, MA, USA
| | - Nagla Elzinad
- Department of Medicine, Renal Section, Boston University School of Medicine, Boston, MA, USA
| | - Xiaosheng Yang
- Department of Medicine, Renal Section, Boston University School of Medicine, Boston, MA, USA
| | - Murad Elsadawi
- Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Adam C Gower
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- Clinical and Translational Science Institute, Boston University School of Medicine, Boston, MA, USA
| | - Mostafa Belghasem
- Department of Biomedical Science, Kaiser Permanente Bernard J Tyson School of Medicine, Pasadena, CA, USA
| | - Tarek Shazly
- College of Engineering & Computing, University of South Carolina, Columbia, SC, USA
| | - Vijaya B Kolachalama
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- Department of Computer Science and Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA
| | - Vipul C Chitalia
- Department of Medicine, Renal Section, Boston University School of Medicine, Boston, MA, USA
- Veterans Affairs Boston Healthcare System, Boston, MA, USA
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7
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Nitz K, Herrmann J, Lerman A, Lutgens E. Costimulatory and Coinhibitory Immune Checkpoints in Atherosclerosis: Therapeutic Targets in Atherosclerosis? JACC Basic Transl Sci 2024; 9:827-843. [PMID: 39070270 PMCID: PMC11282889 DOI: 10.1016/j.jacbts.2023.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 07/30/2024]
Abstract
The benefits of current state-of-the-art treatments to combat atherosclerotic cardiovascular disease (ASCVD) have stagnated. Treatments are mostly based on controlling cardiovascular risk factors, especially hyperlipidemia. Although the most recent advances with PCSK-9 inhibitors support the hyperlipidemia aspect of ASCVD, several lines of experimental evidence have outlined that atherosclerosis is also driven by inflammation. In the past years, phase 1, 2, and 3 clinical trials targeting inflammation to combat ASCVD have revealed that patients do tolerate such immune therapies, show decreases in inflammatory markers, and/or have reductions in cardiovascular endpoints. However, the search for the optimal anti-inflammatory or immune-modulating strategy and the stratification of patients who would benefit from such treatments and appropriate treatment regimens to combat ASCVD is only just beginning. In this review, we focus on immune checkpoint-based therapeutics (costimulation and coinhibition), many of which are already approved by the U.S. Food and Drug Administration for the treatment of cancer or autoimmune diseases, and discuss their use as a novel immunotherapeutic strategy to treat ASCVD.
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Affiliation(s)
- Katrin Nitz
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Joerg Herrmann
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Esther Lutgens
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA
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8
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Obare LM, Temu T, Mallal SA, Wanjalla CN. Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease. Circ Res 2024; 134:1515-1545. [PMID: 38781301 PMCID: PMC11122788 DOI: 10.1161/circresaha.124.323891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
People living with HIV have a 1.5- to 2-fold increased risk of developing cardiovascular disease. Despite treatment with highly effective antiretroviral therapy, people living with HIV have chronic inflammation that makes them susceptible to multiple comorbidities. Several factors, including the HIV reservoir, coinfections, clonal hematopoiesis of indeterminate potential (CHIP), microbial translocation, and antiretroviral therapy, may contribute to the chronic state of inflammation. Within the innate immune system, macrophages harbor latent HIV and are among the prominent immune cells present in atheroma during the progression of atherosclerosis. They secrete inflammatory cytokines such as IL (interleukin)-6 and tumor necrosis-α that stimulate the expression of adhesion molecules on the endothelium. This leads to the recruitment of other immune cells, including cluster of differentiation (CD)8+ and CD4+ T cells, also present in early and late atheroma. As such, cells of the innate and adaptive immune systems contribute to both systemic inflammation and vascular inflammation. On a molecular level, HIV-1 primes the NLRP3 (NLR family pyrin domain containing 3) inflammasome, leading to an increased expression of IL-1β, which is important for cardiovascular outcomes. Moreover, activation of TLRs (toll-like receptors) by HIV, gut microbes, and substance abuse further activates the NLRP3 inflammasome pathway. Finally, HIV proteins such as Nef (negative regulatory factor) can inhibit cholesterol efflux in monocytes and macrophages through direct action on the cholesterol transporter ABCA1 (ATP-binding cassette transporter A1), which promotes the formation of foam cells and the progression of atherosclerotic plaque. Here, we summarize the stages of atherosclerosis in the context of HIV, highlighting the effects of HIV, coinfections, and antiretroviral therapy on cells of the innate and adaptive immune system and describe current and future interventions to reduce residual inflammation and improve cardiovascular outcomes among people living with HIV.
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Affiliation(s)
- Laventa M. Obare
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN (L.M.O., S.A.M., C.N.W.)
| | - Tecla Temu
- Department of Pathology, Harvard Medical School, Boston, MA (T.T.)
| | - Simon A. Mallal
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN (L.M.O., S.A.M., C.N.W.)
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN (S.A.M.)
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN (S.A.M.)
- Institute for Immunology and Infectious Diseases, Murdoch University, WA, Western Australia (S.A.M.)
| | - Celestine N. Wanjalla
- Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN (L.M.O., S.A.M., C.N.W.)
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9
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Zang G, Chen Y, Guo G, Wan A, Li B, Wang Z. Protective Effect of CD137 Deficiency Against Postinfarction Cardiac Fibrosis and Adverse Cardiac Remodeling by ERK1/2 Signaling Pathways. J Cardiovasc Pharmacol 2024; 83:446-456. [PMID: 38416872 DOI: 10.1097/fjc.0000000000001549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 01/29/2024] [Indexed: 03/01/2024]
Abstract
ABSTRACT Myocardial fibrosis, a common complication of myocardial infarction (MI), is characterized by excessive collagen deposition and can result in impaired cardiac function. The specific role of CD137 in the development of post-MI myocardial fibrosis remains unclear. Thus, this study aimed to elucidate the effects of CD137 signaling using CD137 knockout mice and in vitro experiments. CD137 expression levels progressively increased in the heart after MI, particularly in myofibroblast, which play a key role in fibrosis. Remarkably, CD137 knockout mice exhibited improved cardiac function and reduced fibrosis compared with wild-type mice at day 28 post-MI. The use of Masson's trichrome and picrosirius red staining demonstrated a reduction in the infarct area and collagen volume fraction in CD137 knockout mice. Furthermore, the expression of alpha-smooth muscle actin and collagen I, key markers of fibrosis, was decreased in heart tissues lacking CD137. In vitro experiments supported these findings because CD137 depletion attenuated cardiac fibroblast differentiation, and migration, and collagen I synthesis. In addition, the administration of CD137L recombinant protein further promoted alpha-smooth muscle actin expression and collagen I synthesis, suggesting a profibrotic effect. Notably, the application of an inhibitor targeting the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway attenuated the profibrotic effects of CD137L. To conclude, this study provides evidence that CD137 plays a significant role in promoting myocardial fibrosis after MI. Inhibition of CD137 signaling pathways may hold therapeutic potential for mitigating pathological cardiac remodeling and improving post-MI cardiac function.
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MESH Headings
- Animals
- Fibrosis
- Myocardial Infarction/pathology
- Myocardial Infarction/metabolism
- Myocardial Infarction/genetics
- Myocardial Infarction/enzymology
- Myocardial Infarction/physiopathology
- Ventricular Remodeling/drug effects
- Mice, Knockout
- Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism
- Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics
- Mice, Inbred C57BL
- Disease Models, Animal
- Male
- Collagen Type I/metabolism
- Collagen Type I/genetics
- Myofibroblasts/metabolism
- Myofibroblasts/pathology
- Myofibroblasts/enzymology
- MAP Kinase Signaling System
- Myocardium/pathology
- Myocardium/metabolism
- Myocardium/enzymology
- 4-1BB Ligand/metabolism
- 4-1BB Ligand/genetics
- Mitogen-Activated Protein Kinase 3/metabolism
- Mitogen-Activated Protein Kinase 1/metabolism
- Actins/metabolism
- Cells, Cultured
- Signal Transduction
- Cell Movement
- Mice
- Ventricular Function, Left
- Cell Differentiation
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/enzymology
- Myocytes, Cardiac/drug effects
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Affiliation(s)
- Guangyao Zang
- Department of Cardiology, Affiliated Hospital and Institute of Cardiovascular Diseases, Jiangsu University, Zhenjiang, China; and
| | - Yiliu Chen
- Department of Cardiology, Affiliated Hospital and Institute of Cardiovascular Diseases, Jiangsu University, Zhenjiang, China; and
| | - Ge Guo
- Department of Cardiology, Affiliated Hospital and Institute of Cardiovascular Diseases, Jiangsu University, Zhenjiang, China; and
| | - Aijun Wan
- Department of Basic Medical Sciences, School of Nursing, Zhenjiang College, Zhenjiang, China
| | - Bo Li
- Department of Cardiology, Affiliated Hospital and Institute of Cardiovascular Diseases, Jiangsu University, Zhenjiang, China; and
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital and Institute of Cardiovascular Diseases, Jiangsu University, Zhenjiang, China; and
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10
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Luca AC, David SG, David AG, Țarcă V, Pădureț IA, Mîndru DE, Roșu ST, Roșu EV, Adumitrăchioaiei H, Bernic J, Cojocaru E, Țarcă E. Atherosclerosis from Newborn to Adult-Epidemiology, Pathological Aspects, and Risk Factors. Life (Basel) 2023; 13:2056. [PMID: 37895437 PMCID: PMC10608492 DOI: 10.3390/life13102056] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/02/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Cardiovascular disease is the leading cause of mortality and morbidity throughout the world, accounting for 16.7 million deaths each year. The underlying pathological process for the majority of cardiovascular diseases is atherosclerosis, a slowly progressing, multifocal, chronic, immune-inflammatory disease that involves the intima of large and medium-sized arteries. The process of atherosclerosis begins in childhood as fatty streaks-an accumulation of lipids, inflammatory cells, and smooth muscle cells in the arterial wall. Over time, a more complex lesion develops into an atheroma and characteristic fibrous plaques. Atherosclerosis alone is rarely fatal; it is the further changes that render fibrous plaques vulnerable to rupture; plaque rupture represents the most common cause of coronary thrombosis. The prevalence of atherosclerosis is increasing worldwide and more than 50% of people with circulatory disease die of it, mostly in modern societies. Epidemiological studies have revealed several environmental and genetic risk factors that are associated with the early formation of a pathogenic foundation for atherosclerosis, such as dyslipidemia, hypertension, diabetes mellitus, obesity, and smoking. The purpose of this review is to bring together the current information concerning the origin and progression of atherosclerosis in childhood as well as the identification of known risk factors for atherosclerotic cardiovascular disease in children.
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Affiliation(s)
- Alina Costina Luca
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (D.E.M.); (E.V.R.)
| | - Simona Georgiana David
- Saint Mary Emergency Hospital for Children, 700309 Iasi, Romania; (S.G.D.); (A.G.D.); (I.-A.P.); (H.A.)
| | - Alexandru Gabriel David
- Saint Mary Emergency Hospital for Children, 700309 Iasi, Romania; (S.G.D.); (A.G.D.); (I.-A.P.); (H.A.)
| | - Viorel Țarcă
- Department of Preventive Medicine and Interdisciplinarity, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Ioana-Alexandra Pădureț
- Saint Mary Emergency Hospital for Children, 700309 Iasi, Romania; (S.G.D.); (A.G.D.); (I.-A.P.); (H.A.)
| | - Dana Elena Mîndru
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (D.E.M.); (E.V.R.)
| | - Solange Tamara Roșu
- Nursing Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Eduard Vasile Roșu
- Pediatrics Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (A.C.L.); (D.E.M.); (E.V.R.)
| | - Heidrun Adumitrăchioaiei
- Saint Mary Emergency Hospital for Children, 700309 Iasi, Romania; (S.G.D.); (A.G.D.); (I.-A.P.); (H.A.)
| | - Jana Bernic
- Discipline of Pediatric Surgery, “Nicolae Testemițanu” State University of Medicine and Pharmacy, 2025 Chisinau, Moldova;
| | - Elena Cojocaru
- Department of Morphofunctional Sciences I—Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Elena Țarcă
- Surgery II Department—Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
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11
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Salek-Ardakani S, Zajonc DM, Croft M. Agonism of 4-1BB for immune therapy: a perspective on possibilities and complications. Front Immunol 2023; 14:1228486. [PMID: 37662949 PMCID: PMC10469789 DOI: 10.3389/fimmu.2023.1228486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/03/2023] [Indexed: 09/05/2023] Open
Abstract
Costimulatory receptors on immune cells represent attractive targets for immunotherapy given that these molecules can increase the frequency of individual protective immune cell populations and their longevity, as well as enhance various effector functions. 4-1BB, a member of the TNF receptor superfamily, also known as CD137 and TNFRSF9, is one such molecule that is inducible on several cell types, including T cells and NK cells. Preclinical studies in animal models have validated the notion that stimulating 4-1BB with agonist reagents or its natural ligand could be useful to augment conventional T cell and NK cell immunity to protect against tumor growth and against viral infection. Additionally, stimulating 4-1BB can enhance regulatory T cell function and might be useful in the right context for suppressing autoimmunity. Two human agonist antibodies to 4-1BB have been produced and tested in clinical trials for cancer, with variable results, leading to the production of a wealth of second-generation antibody constructs, including bi- and multi-specifics, with the hope of optimizing activity and selectivity. Here, we review the progress to date in agonism of 4-1BB, discuss the complications in targeting the immune system appropriately to elicit the desired activity, together with challenges in engineering agonists, and highlight the untapped potential of manipulating this molecule in infectious disease and autoimmunity.
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Affiliation(s)
| | - Dirk M. Zajonc
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, United States
| | - Michael Croft
- Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA, United States
- Department of Medicine, University of California (UC) San Diego, La Jolla, CA, United States
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12
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Zhang M, Lotfollahzadeh S, Elzinad N, Yang X, Elsadawi M, Gower A, Belghasem M, Shazly T, Kolachalama VB, Chitalia V. Alleviating iatrogenic effects of paclitaxel via anti-inflammatory treatment. RESEARCH SQUARE 2023:rs.3.rs-2487922. [PMID: 36778300 PMCID: PMC9915804 DOI: 10.21203/rs.3.rs-2487922/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Background Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. Objective Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. Methods RNAseq analysis, cell and mouse models. Results RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. Conclusions Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk.
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13
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Yang P, Zang G, Yan Y, Zhong W, Li B, Xu Y, Shao C, Wang Z, Pu J, Yuan W. CD137-CD137L Aggravates Calcification of Vascular Smooth Muscle Cell and Vasculature of ApoE -/- Mice Via Rab7-Mediated Autophagy. J Cardiovasc Transl Res 2022; 15:1297-1314. [PMID: 35763154 DOI: 10.1007/s12265-022-10272-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 05/04/2022] [Indexed: 12/14/2022]
Abstract
Vascular calcification is an independent risk factor for acute cardiovascular events and a predictor of adverse prognosis; the abnormal fusion and degradation of autophagosomes and lysosomes are closely related to the calcification of VSMC and aortic AS plaque in ApoE-/- mice. Rab7 is a member of the Ras protein family and acts as a molecular switch in the fusion between autophagosomes and lysosomes. In this study, we found that the activation of the CD137-CD137L signal promoted calcification by inhibiting the expression and activity of Rab7, which regulates the degradation of autophagic cargo in vascular smooth muscle cells (VSMCs) and aortic atherosclerosis (AS) plaques in ApoE-/- mice. Knockdown of Rab7 impaired its tethering with the downstream molecule FYVE and coiled-coil containing 1 (FYCO1), which transports autophagosomes to lysosomes through microtubule motor kinesins and fuses with lysosomes to degrade the autophagic content. Overexpression of Rab7-alleviated calcification caused by the activation of the CD137 signaling pathway. In addition, FYCO1 knockdown promoted calcification even though the expression and activity of Rab7 were normal. Our results suggest that Rab7 is the target of CD137 signaling; Rab7 cannot interact with its downstream molecule FYCO1 when its activity and expression were inhibited by the activation of CD137 signaling pathway, thus inhibiting the autophagic degradation and promoting calcification.
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Affiliation(s)
- Ping Yang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
- School of Medicine, Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Guangyao Zang
- School of Medicine, Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Yang Yan
- Department of Cardiology Ren Ji Hospital Affiliated to Shanghai, Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Zhong
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
- School of Medicine, Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Bo Li
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
- School of Medicine, Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Yao Xu
- School of Medicine, Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Chen Shao
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China
| | - Jun Pu
- Department of Cardiology Ren Ji Hospital Affiliated to Shanghai, Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Yuan
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Jiangsu Province, 212001, Zhenjiang, China.
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14
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Cao G, Xuan X, Hu J, Zhang R, Jin H, Dong H. How vascular smooth muscle cell phenotype switching contributes to vascular disease. Cell Commun Signal 2022; 20:180. [PMID: 36411459 PMCID: PMC9677683 DOI: 10.1186/s12964-022-00993-2] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 10/22/2022] [Indexed: 11/22/2022] Open
Abstract
Vascular smooth muscle cells (VSMCs) are the most abundant cell in vessels. Earlier experiments have found that VSMCs possess high plasticity. Vascular injury stimulates VSMCs to switch into a dedifferentiated type, also known as synthetic VSMCs, with a high migration and proliferation capacity for repairing vascular injury. In recent years, largely owing to rapid technological advances in single-cell sequencing and cell-lineage tracing techniques, multiple VSMCs phenotypes have been uncovered in vascular aging, atherosclerosis (AS), aortic aneurysm (AA), etc. These VSMCs all down-regulate contractile proteins such as α-SMA and calponin1, and obtain specific markers and similar cellular functions of osteoblast, fibroblast, macrophage, and mesenchymal cells. This highly plastic phenotype transformation is regulated by a complex network consisting of circulating plasma substances, transcription factors, growth factors, inflammatory factors, non-coding RNAs, integrin family, and Notch pathway. This review focuses on phenotypic characteristics, molecular profile and the functional role of VSMCs phenotype landscape; the molecular mechanism regulating VSMCs phenotype switching; and the contribution of VSMCs phenotype switching to vascular aging, AS, and AA. Video Abstract.
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Affiliation(s)
- Genmao Cao
- grid.452845.a0000 0004 1799 2077Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, China
| | - Xuezhen Xuan
- grid.452845.a0000 0004 1799 2077Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, China
| | - Jie Hu
- grid.452845.a0000 0004 1799 2077Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, China
| | - Ruijing Zhang
- grid.452845.a0000 0004 1799 2077Department of Nephrology, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, China
| | - Haijiang Jin
- grid.452845.a0000 0004 1799 2077Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, China
| | - Honglin Dong
- grid.452845.a0000 0004 1799 2077Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, China
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15
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Sudhahar V, Shi Y, Kaplan JH, Ushio-Fukai M, Fukai T. Whole-Transcriptome Sequencing Analyses of Nuclear Antixoxidant-1 in Endothelial Cells: Role in Inflammation and Atherosclerosis. Cells 2022; 11:2919. [PMID: 36139494 PMCID: PMC9496719 DOI: 10.3390/cells11182919] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/08/2022] [Accepted: 09/15/2022] [Indexed: 11/26/2022] Open
Abstract
Inflammation, oxidative stress, and copper (Cu) play an important role in cardiovascular disease, including atherosclerosis. We previously reported that cytosolic Cu chaperone antioxidant-1 (Atox1) translocates to the nucleus in response to inflammatory cytokines or exogenous Cu and that Atox1 is localized at the nucleus in the endothelium of inflamed atherosclerotic aorta. However, the roles of nuclear Atox1 and their function are poorly understood. Here we showed that Atox1 deficiency in ApoE-/- mice with a Western diet exhibited a significant reduction of atherosclerotic lesion formation. In vitro, adenovirus-mediated overexpression of nuclear-targeted Atox1 (Ad-Atox1-NLS) in cultured human endothelial cells (ECs) increased monocyte adhesion and reactive oxygen species (ROS) production compared to control cells (Ad-null). To address the underlying mechanisms, we performed genome-wide mapping of Atox1-regulated targets in ECs, using an unbiased systemic approach integrating sequencing data. Combination of ChIP-Seq and RNA-Seq analyses in ECs transfected with Ad-Atox1-NLS or Ad-null identified 1387 differentially expressed genes (DEG). Motif enrichment assay and KEGG pathway enrichment analysis revealed that 248 differentially expressed genes, including inflammatory and angiogenic genes, were regulated by Atox1-NLS, which was then confirmed by real-time qPCR. Among these genes, functional analysis of inflammatory responses identified CD137, CSF1, and IL5RA as new nuclear Atox1-targeted inflammatory genes, while CD137 is also a key regulator of Atox1-NLS-induced ROS production. These findings uncover new nuclear Atox1 downstream targets involved in inflammation and ROS production and provide insights into the nuclear Atox1 as a potential therapeutic target for the treatment of inflammatory diseases such as atherosclerosis.
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Affiliation(s)
- Varadarajan Sudhahar
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30901, USA
| | - Yang Shi
- Department of Population Health Science, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Jack H. Kaplan
- Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA
| | - Masuko Ushio-Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Medicine (Cardiology), Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Tohru Fukai
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Charlie Norwood Veterans Affairs Medical Center, Augusta, GA 30901, USA
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16
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Kim AMJ, Nemeth MR, Lim SO. 4-1BB: A promising target for cancer immunotherapy. Front Oncol 2022; 12:968360. [PMID: 36185242 PMCID: PMC9515902 DOI: 10.3389/fonc.2022.968360] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Immunotherapy, powered by its relative efficacy and safety, has become a prominent therapeutic strategy utilized in the treatment of a wide range of diseases, including cancer. Within this class of therapeutics, there is a variety of drug types such as immune checkpoint blockade therapies, vaccines, and T cell transfer therapies that serve the purpose of harnessing the body’s immune system to combat disease. Of these different types, immune checkpoint blockades that target coinhibitory receptors, which dampen the body’s immune response, have been widely studied and established in clinic. In contrast, however, there remains room for the development and improvement of therapeutics that target costimulatory receptors and enhance the immune response against tumors, one of which being the 4-1BB (CD137/ILA/TNFRSF9) receptor. 4-1BB has been garnering attention as a promising therapeutic target in the setting of cancer, amongst other diseases, due to its broad expression profile and ability to stimulate various signaling pathways involved in the generation of a potent immune response. Since its discovery and demonstration of potential as a clinical target, major progress has been made in the knowledge of 4-1BB and the development of clinical therapeutics that target it. Thus, we seek to summarize and provide a comprehensive update and outlook on those advancements in the context of cancer and immunotherapy.
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Affiliation(s)
- Alyssa Min Jung Kim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Macy Rose Nemeth
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, United States
- Purdue Institute of Drug Discovery, Purdue University, West Lafayette, IN, United States
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, United States
- *Correspondence: Seung-Oe Lim,
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17
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Pandey AK, Waldeck-Weiermair M, Wells QS, Xiao W, Yadav S, Eroglu E, Michel T, Loscalzo J. Expression of CD70 Modulates Nitric Oxide and Redox Status in Endothelial Cells. Arterioscler Thromb Vasc Biol 2022; 42:1169-1185. [PMID: 35924558 PMCID: PMC9394499 DOI: 10.1161/atvbaha.122.317866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Endothelial dysfunction is a critical component in the pathogenesis of cardiovascular diseases and is closely associated with nitric oxide (NO) levels and oxidative stress. Here, we report on novel findings linking endothelial expression of CD70 (also known as CD27 ligand) with alterations in NO and reactive oxygen species. METHODS CD70 expression was genetically manipulated in human aortic and pulmonary artery endothelial cells. Intracellular NO and hydrogen peroxide (H2O2) were measured using genetically encoded biosensors, and cellular phenotypes were assessed. RESULTS An unbiased phenome-wide association study demonstrated that polymorphisms in CD70 associate with vascular phenotypes. Endothelial cells treated with CD70-directed short-interfering RNA demonstrated impaired wound closure, decreased agonist-stimulated NO levels, and reduced eNOS (endothelial nitric oxide synthase) protein. These changes were accompanied by reduced NO bioactivity, increased 3-nitrotyrosine levels, and a decrease in the eNOS binding partner heat shock protein 90. Following treatment with the thioredoxin inhibitor auranofin or with agonist histamine, intracellular H2O2 levels increased up to 80% in the cytosol, plasmalemmal caveolae, and mitochondria. There was increased expression of NADPH oxidase 1 complex and gp91phox; expression of copper/zinc and manganese superoxide dismutases was also elevated. CD70 knockdown reduced levels of the H2O2 scavenger catalase; by contrast, glutathione peroxidase 1 expression and activity were increased. CD70 overexpression enhanced endothelial wound closure, increased NO levels, and attenuated the reduction in eNOS mRNA induced by TNFα. CONCLUSIONS Taken together, these data establish CD70 as a novel regulatory protein in endothelial NO and reactive oxygen species homeostasis, with implications for human vascular disease.
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Affiliation(s)
- Arvind K. Pandey
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (A.K.P., M.W.-W., W.X., S.Y., T.M., J.L.)
| | - Markus Waldeck-Weiermair
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (A.K.P., M.W.-W., W.X., S.Y., T.M., J.L.)
| | - Quinn S. Wells
- Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University, Nashville, TN (Q.S.W.)
| | - Wusheng Xiao
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (A.K.P., M.W.-W., W.X., S.Y., T.M., J.L.)
| | - Shambhu Yadav
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (A.K.P., M.W.-W., W.X., S.Y., T.M., J.L.)
| | - Emrah Eroglu
- Faculty for Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey (E.E.)
| | - Thomas Michel
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (A.K.P., M.W.-W., W.X., S.Y., T.M., J.L.)
| | - Joseph Loscalzo
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (A.K.P., M.W.-W., W.X., S.Y., T.M., J.L.)
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18
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Sun R, Lim SO. FBXL20-mediated ubiquitination triggers the proteasomal degradation of 4-1BB. FEBS J 2022; 289:4549-4563. [PMID: 35112462 DOI: 10.1111/febs.16383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/27/2021] [Accepted: 02/01/2022] [Indexed: 12/16/2022]
Abstract
4-1BB [tumor necrosis factor receptor superfamily (TNFRSF9), CD137) is a critical immune stimulator that sustains T cell activity and antitumor immune response. The strategy to eliminate cancers by agonistically targeting 4-1BB is under clinical investigation. As a protein expressed in an inducible manner, 4-1BB is under tight control on both transcription and translation levels to maintain its homeostasis. So far, the mechanisms underlying the transcriptional activation of 4-1BB have been well-interpreted; however, it remains inexplicit how 4-1BB is regulated on the protein level. In this study, we presented experimental evidence supporting that 4-1BB, especially the heavily N-glycosylated (mature) form, is polyubiquitinated and subjected to the ubiquitin-proteasomal system for degradation. By performing proximity-dependent biotin identification screening coupled with biochemical assays, we identified that F-box/LRR-repeat protein 20 acts as the E3 ligase that promotes the polyubiquitination of 4-1BB at the intracellular domain. Our data provided mechanistic insight into 4-1BB regulation on the protein level by unmasking, for the first time, a posttranslational mechanism governing 4-1BB abundance in cells. The findings of this study could potentially guide the development of 4-1BB-targeted therapy for cancers as well as other immune disorders.
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Affiliation(s)
- Ruoxuan Sun
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA
| | - Seung-Oe Lim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.,Purdue Institute of Drug Discovery, Purdue University, West Lafayette, IN, USA.,Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA
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19
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Fournier B, Hoshino A, Bruneau J, Bachelet C, Fusaro M, Klifa R, Lévy R, Lenoir C, Soudais C, Picard C, Blanche S, Castelle M, Moshous D, Molina T, Defachelles AS, Neven B, Latour S. Inherited TNFSF9 deficiency causes broad Epstein-Barr virus infection with EBV+ smooth muscle tumors. J Exp Med 2022; 219:213262. [PMID: 35657354 PMCID: PMC9170382 DOI: 10.1084/jem.20211682] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 03/16/2022] [Accepted: 04/25/2022] [Indexed: 01/07/2023] Open
Abstract
Epstein-Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137-CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.
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Affiliation(s)
- Benjamin Fournier
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France,Paris Cité University, Imagine Institute, Paris, France,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Akihiro Hoshino
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France
| | - Julie Bruneau
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Camille Bachelet
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France,Paris Cité University, Imagine Institute, Paris, France
| | - Mathieu Fusaro
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France,Paris Cité University, Imagine Institute, Paris, France,Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Roman Klifa
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Romain Lévy
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Christelle Lenoir
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France
| | - Claire Soudais
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France,Paris Cité University, Imagine Institute, Paris, France
| | - Capucine Picard
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France,Paris Cité University, Imagine Institute, Paris, France,Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Stéphane Blanche
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Martin Castelle
- Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Despina Moshous
- Paris Cité University, Imagine Institute, Paris, France,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Thierry Molina
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | | | - Bénédicte Neven
- Paris Cité University, Imagine Institute, Paris, France,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Institut national de la santé et de la recherche médicale UMR 1163, Paris, France,Paris Cité University, Imagine Institute, Paris, France,Correspondence to Sylvain Latour:
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20
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Aghamajidi A, Gorgani M, Shahba F, Shafaghat Z, Mojtabavi N. The potential targets in immunotherapy of atherosclerosis. Int Rev Immunol 2021; 42:199-216. [PMID: 34779341 DOI: 10.1080/08830185.2021.1988591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Cardiovascular disease is the most common cause of death, which has the highest mortality rate worldwide. Although a diverse range of inflammatory diseases can affect the cardiovascular system, however, heart failure and stroke occur due to atherosclerosis. Atherosclerosis is a chronic autoinflammatory disease of small to large vessels in which different immune mediators are involved in lipid plaque formation and inflammatory vascular remodeling process. A better understanding of the pathophysiology of atherosclerosis may lead to uncovering immunomodulatory therapies. Despite present diagnostic and therapeutic methods, the lack of immunotherapy in the prevention and treatment of atherosclerosis is perceptible. In this review, we will discuss the promising immunological-based therapeutics and novel preventive approaches for atherosclerosis. This study could provide new insights into a better perception of targeted therapeutic pathways and biological therapies.
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Affiliation(s)
- Azin Aghamajidi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Melika Gorgani
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.,Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Faezeh Shahba
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Shafaghat
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.,Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
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21
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Tan L, Xu Q, Shi R, Zhang G. Bioinformatics analysis reveals the landscape of immune cell infiltration and immune-related pathways participating in the progression of carotid atherosclerotic plaques. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 49:96-107. [PMID: 33480285 DOI: 10.1080/21691401.2021.1873798] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Atherosclerosis is a systemic disease associated with inflammatory cell infiltration and activation of immune-related pathways. In our study, we aimed to uncover immune-related changes and explore novel immunological features in the development of carotid atherosclerotic plaques. First, we applied integrated bioinformatics methods, including CIBERSORT and gene set enrichment analysis (GSEA). The gene expression matrices GSE28829, GSE41571, and GSE43292 were obtained from the Gene Expression Omnibus (GEO) dataset. After a series of data pre-processing steps, the resulting combined expression matrices were analysed using the CIBERSORT, GSEA, and Cluster Profiler packages. After the comparison and analysis between the carotid atherosclerotic plaques in the early and advanced stages, we discovered that there is a higher percentage of activated memory CD4 T cells and a lower percentage of resting memory CD4 cells in advanced-stage plaques. Moreover, activation of memory CD4 T cells can promote the development of carotid atherosclerotic plaques. Additionally, FOXP3+ Treg cell maturation can also participate in the progression of carotid plaques.
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Affiliation(s)
- Liao Tan
- Department of Cardiology, The Third Xiangya Hospital, Central South University Changsha, Hunan, China.,Institute of Hypertension, Central South University, Changsha, China
| | - Qian Xu
- Institute of Hypertension, Central South University, Changsha, China.,Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ruizheng Shi
- Department of Cardiology, The Third Xiangya Hospital, Central South University Changsha, Hunan, China.,Institute of Hypertension, Central South University, Changsha, China
| | - Guogang Zhang
- Department of Cardiology, The Third Xiangya Hospital, Central South University Changsha, Hunan, China.,Institute of Hypertension, Central South University, Changsha, China.,Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China
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22
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Yuan W, Xu C, Li B, Xia H, Pan Y, Zhong W, Xu L, Chen R, Wang B. Contributions of Costimulatory Molecule CD137 in Endothelial Cells. J Am Heart Assoc 2021; 10:e020721. [PMID: 34027676 PMCID: PMC8483511 DOI: 10.1161/jaha.120.020721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
CD137 (4-1BB, tumor necrosis factor receptor superfamily 9) is a surface glycoprotein of the tumor necrosis factor receptor family that can be induced on a variety of immunocytes and nonimmune cells, including endothelial cells and smooth muscle cells. The importance of CD137 in immune response has been well recognized; however, the precise biological effects and underlying mechanisms of CD137 in endothelial cells are unclear. A single layer of cells called the endothelium constitutes the innermost layer of blood vessels including larger arteries, veins, the capillaries, and the lymphatic vessels. It not only acts as an important functional interface, but also participates in local inflammatory response. This review covers recent findings to illuminate the role of CD137 in endothelial cells in different pathophysiologic settings.
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Affiliation(s)
- Wei Yuan
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Chong Xu
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Bo Li
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Hao Xia
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Yingjie Pan
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Wei Zhong
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Liangjie Xu
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Rui Chen
- Department of Cardiology Affiliated Hospital of Jiangsu University Zhenjiang China
| | - Bin Wang
- Department of Geriatrics Union Hospital Tongji Medical CollegeHuazhong University of Science and Technology Wuhan China
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23
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Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, Lutgens E. Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans. Eur Heart J 2021; 41:2938-2948. [PMID: 32728688 DOI: 10.1093/eurheartj/ehaa484] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 03/21/2020] [Accepted: 05/20/2020] [Indexed: 12/18/2022] Open
Abstract
AIMS GITR-a co-stimulatory immune checkpoint protein-is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD). METHODS AND RESULTS GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (IL)-6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr-/-Apoe-/- mice was reduced, and plaques had a favourable phenotype with less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr-/-Apoe-/- and Apoe-/- monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr-/-Apoe-/- monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity. CONCLUSION Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.
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Affiliation(s)
- Annelie Shami
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Dorothee Atzler
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany.,Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians Universität, München, Germany.,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Laura A Bosmans
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Holger Winkels
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany.,Department of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Svenja Meiler
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany
| | - Michael Lacy
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany.,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Claudia van Tiel
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Remco Ta Megens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany.,Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
| | - Katrin Nitz
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany
| | - Jeroen Baardman
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Pascal Kusters
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Tom Seijkens
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Christina Buerger
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany
| | - Aleksandar Janjic
- Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians-Universität, München, Martinsried, Germany
| | - Carlo Riccardi
- Department of Medicine, Università degli Studi di Perugia, Perugia, Italy
| | - Andreas Edsfeldt
- Department of Clinical Sciences Malmö, Lund University, Clinical Research Center, Malmö, Sweden.,Department of Cardiology, Skåne University Hospital, Lund University, Sweden
| | - Claudia Monaco
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK
| | - Mat Daemen
- Department of Pathology, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Menno P J de Winther
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany
| | - Jan Nilsson
- Department of Clinical Sciences Malmö, Lund University, Clinical Research Center, Malmö, Sweden
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany.,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.,Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
| | - Norbert Gerdes
- Division of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Isabel Gonçalves
- Department of Clinical Sciences Malmö, Lund University, Clinical Research Center, Malmö, Sweden.,Department of Cardiology, Skåne University Hospital, Lund University, Sweden
| | - Esther Lutgens
- Experimental Vascular Biology Division, Department of Medical Biochemistry, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany.,German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
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24
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Fournier B, Latour S. Immunity to EBV as revealed by immunedeficiencies. Curr Opin Immunol 2021; 72:107-115. [PMID: 33989894 DOI: 10.1016/j.coi.2021.04.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/29/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023]
Abstract
Epstein-Barr virus infection is the most common viral latent infection in humans and represents one prototypical model to study immunity to viral infections. In that respect, inborn errors of immunity (IEIs) or primary immunodeficiencies (PIDs) predisposing to severe and chronic EBV infections provide peculiar examples to decipher-specific molecular and cellular components involved in the immune control of EBV-infected cells. Herein, we discuss the recent knowledge and concepts arising from these studies, with a particular focus on 'atypical' EBV infections when EBV enters T, NK and smooth muscle cells, instead of the common 'typical' infection of B cells.
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Affiliation(s)
- Benjamin Fournier
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France; Université de Paris, F75006 Paris, France; Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades, Paris, France
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France; Université de Paris, F75006 Paris, France.
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25
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Gallina AL, Rykaczewska U, Wirka RC, Caravaca AS, Shavva VS, Youness M, Karadimou G, Lengquist M, Razuvaev A, Paulsson-Berne G, Quertermous T, Gisterå A, Malin SG, Tarnawski L, Matic L, Olofsson PS. AMPA-Type Glutamate Receptors Associated With Vascular Smooth Muscle Cell Subpopulations in Atherosclerosis and Vascular Injury. Front Cardiovasc Med 2021; 8:655869. [PMID: 33959644 PMCID: PMC8093397 DOI: 10.3389/fcvm.2021.655869] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/11/2021] [Indexed: 12/22/2022] Open
Abstract
Objectives and Aims: Vascular smooth muscle cells (VSMCs) are key constituents of both normal arteries and atherosclerotic plaques. They have an ability to adapt to changes in the local environment by undergoing phenotypic modulation. An improved understanding of the mechanisms that regulate VSMC phenotypic changes may provide insights that suggest new therapeutic targets in treatment of cardiovascular disease (CVD). The amino-acid glutamate has been associated with CVD risk and VSMCs metabolism in experimental models, and glutamate receptors regulate VSMC biology and promote pulmonary vascular remodeling. However, glutamate-signaling in human atherosclerosis has not been explored. Methods and Results: We identified glutamate receptors and glutamate metabolism-related enzymes in VSMCs from human atherosclerotic lesions, as determined by single cell RNA sequencing and microarray analysis. Expression of the receptor subunits glutamate receptor, ionotropic, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type subunit 1 (GRIA1) and 2 (GRIA2) was restricted to cells of mesenchymal origin, primarily VSMCs, as confirmed by immunostaining. In a rat model of arterial injury and repair, changes of GRIA1 and GRIA2 mRNA level were most pronounced at time points associated with VSMC proliferation, migration, and phenotypic modulation. In vitro, human carotid artery SMCs expressed GRIA1, and selective AMPA-type receptor blocking inhibited expression of typical contractile markers and promoted pathways associated with VSMC phenotypic modulation. In our biobank of human carotid endarterectomies, low expression of AMPA-type receptor subunits was associated with higher content of inflammatory cells and a higher frequency of adverse clinical events such as stroke. Conclusion: AMPA-type glutamate receptors are expressed in VSMCs and are associated with phenotypic modulation. Patients suffering from adverse clinical events showed significantly lower mRNA level of GRIA1 and GRIA2 in their atherosclerotic lesions compared to asymptomatic patients. These results warrant further mapping of neurotransmitter signaling in the pathogenesis of human atherosclerosis.
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Affiliation(s)
- Alessandro L Gallina
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Urszula Rykaczewska
- Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Robert C Wirka
- Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, United States
- McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, United States
| | - April S Caravaca
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Vladimir S Shavva
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Mohamad Youness
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
- Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Glykeria Karadimou
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Mariette Lengquist
- Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Anton Razuvaev
- Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Gabrielle Paulsson-Berne
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Thomas Quertermous
- Division of Cardiovascular Medicine and Cardiovascular Institute, School of Medicine, Stanford University, California, CA, United States
| | - Anton Gisterå
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Stephen G Malin
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Laura Tarnawski
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Ljubica Matic
- Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Peder S Olofsson
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, United States
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26
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Valenzuela NM. IFNγ, and to a Lesser Extent TNFα, Provokes a Sustained Endothelial Costimulatory Phenotype. Front Immunol 2021; 12:648946. [PMID: 33936069 PMCID: PMC8082142 DOI: 10.3389/fimmu.2021.648946] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/25/2021] [Indexed: 02/05/2023] Open
Abstract
Background Vascular endothelial cells (EC) are critical for regulation of local immune responses, through coordination of leukocyte recruitment from the blood and egress into the tissue. Growing evidence supports an additional role for endothelium in activation and costimulation of adaptive immune cells. However, this function remains somewhat controversial, and the full repertoire and durability of an enhanced endothelial costimulatory phenotype has not been wholly defined. Methods Human endothelium was stimulated with continuous TNFα or IFNγ for 1-48hr; or primed with TNFα or IFNγ for only 3hr, before withdrawal of stimulus for up to 45hr. Gene expression of cytokines, costimulatory molecules and antigen presentation molecules was measured by Nanostring, and publicly available datasets of EC stimulation with TNFα or IFNγ were leveraged to further corroborate the results. Cell surface protein expression was detected by flow cytometry, and secretion of cytokines was assessed by Luminex and ELISA. Key findings were confirmed in primary human endothelial cells from 4-6 different vascular beds. Results TNFα triggered mostly positive immune checkpoint molecule expression on endothelium, including CD40, 4-1BB, and ICOSLG but in the context of only HLA class I and immunoproteasome subunits. IFNγ promoted a more tolerogenic phenotype of high PD-L1 and PD-L2 expression with both HLA class I and class II molecules and antigen processing genes. Both cytokines elicited secretion of IL-15 and BAFF/BLyS, with TNFα stimulated EC additionally producing IL-6, TL1A and IL-1β. Moreover, endothelium primed for a short period (3hr) with TNFα mostly failed to alter the costimulatory phenotype 24-48hr later, with only somewhat augmented expression of HLA class I. In contrast, brief exposure to IFNγ was sufficient to cause late expression of antigen presentation, cytokines and costimulatory molecules. In particular HLA class I, PD-1 ligand and cytokine expression was markedly high on endothelium two days after IFNγ was last present. Conclusions Endothelia from multiple vascular beds possess a wide range of other immune checkpoint molecules and cytokines that can shape the adaptive immune response. Our results further demonstrate that IFNγ elicits prolonged signaling that persists days after initiation and is sufficient to trigger substantial gene expression changes and immune phenotype in vascular endothelium.
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Affiliation(s)
- Nicole M Valenzuela
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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27
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Ferrari PF, Zattera E, Pastorino L, Perego P, Palombo D. Dextran/poly-L-arginine multi-layered CaCO 3-based nanosystem for vascular drug delivery. Int J Biol Macromol 2021; 177:548-558. [PMID: 33577822 DOI: 10.1016/j.ijbiomac.2021.02.058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/31/2021] [Accepted: 02/07/2021] [Indexed: 12/26/2022]
Abstract
The development of heterogeneous drug delivery systems leads to innovative strategies for targeted therapy of common pathologies, such as cancer, immunological and neurological disorders. Nowadays, it is possible to choose among a great variety of nanoparticles on the basis of the needs they have to satisfy. However, a candidate for the treatment of cardiovascular pathologies is still missing. In this context, a targeted therapy implies the conceptualization of nanoparticles that take active part in the treatment of vascular pathologies. The aim of this work was to provide a method to produce multi-layered calcium carbonate (CaCO3) nanoparticles encapsulating a model protein, bovine serum albumin, with model antibodies on their surface. CaCO3 nanoparticles were produced by the combination of complex coacervation and mineralization and were engineered using layer-by-layer technique with a polysaccharide, dextran sulfate, and a homo-poly-amino acid, poly-L-arginine. Morphology, biocompatibility, cellular uptake, influence on cell expression of the inflammatory marker matrix metalloproteinase-9, and hemocompatibility of the nanoparticles were studied. The presence of the dextran/poly-L-arginine layers did not negatively affect the nanoparticle overall characteristics and they did not trigger proinflammatory response in vitro. Taking together all the obtained results, we consider the proposed CaCO3 nanoparticles as a promising tool in cardiovascular field.
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Affiliation(s)
- Pier Francesco Ferrari
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, viale Benedetto XV, 6, 16132 Genoa, Italy.
| | - Elena Zattera
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, viale Benedetto XV, 6, 16132 Genoa, Italy
| | - Laura Pastorino
- Department of Informatics, Bioengineering, Robotics and Systems Engineering, University of Genoa, via Opera Pia, 13, 16145 Genoa, Italy
| | - Patrizia Perego
- Department of Civil, Chemical and Environmental Engineering, University of Genoa, via Opera Pia, 15, 16145 Genoa, Italy; Research Center for Biologically Inspired Engineering in Vascular Medicine and Longevity, University of Genoa, via Montallegro, 1, 16145 Genoa, Italy
| | - Domenico Palombo
- Department of Surgical and Integrated Diagnostic Sciences, University of Genoa, viale Benedetto XV, 6, 16132 Genoa, Italy; Research Center for Biologically Inspired Engineering in Vascular Medicine and Longevity, University of Genoa, via Montallegro, 1, 16145 Genoa, Italy; Vascular and Endovascular Surgery Unit, IRCCS Ospedale Policlinico San Martino, largo Rosanna Benzi, 10, 16132 Genoa, Italy
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28
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Abstract
Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8+ T cells ameliorates atherosclerosis. CD8+ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8+ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8+ T cells and their cytotoxic activity. CD8+ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8+ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8+ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8+ T cells in atherosclerosis.
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29
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Faghih Z, Taherifard E, Daneshmand A, Talei A, Erfani N. OX40 genetic variations in patients with breast cancer: a case-control study. Br J Biomed Sci 2020; 78:44-46. [PMID: 32921275 DOI: 10.1080/09674845.2020.1776587] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Z Faghih
- Shiraz Institute for Cancer Research
| | | | | | - A Talei
- Breast Disease Research Center
| | - N Erfani
- Shiraz Institute for Cancer Research.,Department of Immunology, School of Medicine, Shiraz University of Medical Sciences , Shiraz, Iran
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30
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Activating CD137 Signaling Promotes Sprouting Angiogenesis via Increased VEGFA Secretion and the VEGFR2/Akt/eNOS Pathway. Mediators Inflamm 2020; 2020:1649453. [PMID: 33162828 PMCID: PMC7604604 DOI: 10.1155/2020/1649453] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/13/2020] [Accepted: 08/03/2020] [Indexed: 11/18/2022] Open
Abstract
Combination of antiangiogenesis and immunotherapy may be an effective strategy for treatment of solid tumors. Our previous work reported that activation of CD137 signaling promotes intraplaque angiogenesis. A number of studies have demonstrated that vascular endothelial growth factor receptor 2 (VEGFR2) is a key target for angiogenesis. However, it is unknown whether CD137-mediated angiogenesis is related to VEGFR2. In this study, we investigated the effect of CD137 on the VEGFR2 expression and explored the underlying mechanisms of CD137-mediated angiogenesis. Knock-out of CD137 in ApoE−/− mice significantly decreased neovessel density in atherosclerotic plaques. CD137 silencing or inhibition attenuated endothelial cell (ECs) proliferation, migration, and tube formation. We found activation of CD137 signaling for increased VEGFR2 transcription and translation steadily. Moreover, CD137 signaling activated phosphorylated VEGFR2 (Tyr1175) and the downstream Akt/eNOS pathway, whereas neutralizing CD137 signaling weakened the activation of VEGFR2 and the downstream Akt/eNOS pathway. The aortic ring assay further demonstrated that CD137 signaling promoted ECc sprouting. Inhibition of VEGFR2 by siRNA or XL184 (cabozantinib) and inhibition of downstream signaling by LY294002 (inhibits AKT activation) and L-NAME (eNOS inhibitor) remarkably abolished proangiogenic effects of CD137 signaling both in vitro and ex vivo. In addition, the condition medium from CD137-activated ECs and vascular endothelial growth factor A (VEGFA) had similar effects on ECs that expressed high VEGFR2. Additionally, activating CD137 signaling promoted endothelial secretion of VEGFA, while blocking CD137 signaling attenuated VEGFA secretion. In conclusion, activation of CD137 signaling promoted sprouting angiogenesis by increased VEGFA secretion and the VEGFR2/Akt/eNOS pathway. These findings provide a basis for stabilizing intraplaque angiogenesis through VEGFR2 intervatioin, as well as cancer treatment via combination of CD137 agonists and specific VEGFR2 inhibitors.
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Poly (Lactic- co-Glycolic Acid) Nanoparticles and Nanoliposomes for Protein Delivery in Targeted Therapy: A Comparative In Vitro Study. Polymers (Basel) 2020; 12:polym12112566. [PMID: 33139610 PMCID: PMC7692461 DOI: 10.3390/polym12112566] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Over the previous years, the design, development, and potential application of nanocarriers in the medical field have been intensively studied for their ability to preserve drug properties, especially their pharmacological activity, and to improve their bioavailability. This work is a comparative study between two different types of nanocarriers, poly (lactic-co-glycolic acid)-based nanoparticles and phosphatidylcholine-based nanoliposomes, both prepared for the encapsulation of bovine serum albumin as a model protein. Polymeric nanoparticles were produced using the double emulsion water-oil-water evaporation method, whereas nanoliposomes were obtained by the thin-film hydration method. Both nanocarriers were characterized by morphological analysis, particle mean size, particle size distribution, and protein entrapment efficiency. Invitro release studies were performed for 12 days at 37 °C. In order to explore a possible application of these nanocarriers for a targeted therapy in the cardiovascular field, hemolytic activity and biocompatibility, in terms of cell viability, were performed by using human red blood cells and EA.hy926 human endothelial cell line, respectively.
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Sun L, Zhang W, Zhao Y, Wang F, Liu S, Liu L, Zhao L, Lu W, Li M, Xu Y. Dendritic Cells and T Cells, Partners in Atherogenesis and the Translating Road Ahead. Front Immunol 2020; 11:1456. [PMID: 32849502 PMCID: PMC7403484 DOI: 10.3389/fimmu.2020.01456] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 06/04/2020] [Indexed: 12/13/2022] Open
Abstract
Atherosclerosis is a chronic process associated with arterial inflammation, the accumulation of lipids, plaque formation in vessel walls, and thrombosis with late mortal complications such as myocardial infarction and ischemic stroke. Immune and inflammatory responses have significant effects on every phase of atherosclerosis. Increasing evidence has shown that both innate and adaptive “arms” of the immune system play important roles in regulating the progression of atherosclerosis. Accumulating evidence suggests that a unique type of innate immune cell, termed dendritic cells (DCs), play an important role as central instigators, whereas adaptive immune cells, called T lymphocytes, are crucial as active executors of the DC immunity in atherogenesis. These two important immune cell types work in pairs to establish pro-atherogenic or atheroprotective immune responses in vascular tissues. Therefore, understanding the role of DCs and T cells in atherosclerosis is extremely important. Here, in this review, we will present a complete overview, based on existing knowledge of these two cell types in the atherosclerotic microenvironment, and discuss some of the novel means of targeting DCs and T cells as therapeutic tactics for the treatment of atherosclerosis.
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Affiliation(s)
- Li Sun
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Wenjie Zhang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Yanfang Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Fengge Wang
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Shan Liu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Lei Liu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Lin Zhao
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Wei Lu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Minghui Li
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
| | - Yuekang Xu
- Anhui Provincial Key Laboratory for Conservation and Exploitation of Biological Resources, College of Life Science, Anhui Normal University, Wuhu, China
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CD137 Signaling Promotes Endothelial Apoptosis by Inhibiting Nrf2 Pathway, and Upregulating NF- κB Pathway. Mediators Inflamm 2020; 2020:4321912. [PMID: 32587470 PMCID: PMC7294359 DOI: 10.1155/2020/4321912] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 05/02/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
Background Endothelial dysfunction and apoptosis resulting from oxidative stress can lead to the development of atherosclerosis. Our group has previously showed that CD137 signaling contributes to the progression of atherosclerosis and the vulnerability of plaques. The aim of this study is to investigate the effects of CD137 signaling in atherosclerosis on endothelial cells (ECs) apoptosis and to explore the underlying mechanisms. Methods Serum samples were collected from 11 patients with acute myocardial infarction and 4 controls. Peritoneal injection of agonist-CD137 recombinant protein in ApoE−/− mice was used to determine whether CD137 signaling can promote apoptosis in vivo, and human umbilical vein endothelial cells treated with agonist-CD137 recombinant protein, M5580 (a Nrf2 pathway agonist) and CAPE (a NF-κB pathway inhibitor) were used to explore the effect of Nrf2 and NF-κB pathway in CD137 signaling-induced ECs apoptosis in vitro. Results ELISA showed that Bcl-2 in the serum of AMI patients was lower than that of the control group, while TNF-α and sCD137 were higher than that of the control group. Confocal microscopy and Western blot analysis showed that the nuclear translocation of Nrf2 in the agonist-CD137 group was significantly inhibited, and the expression of its downstream antioxidant enzymes was also decreased when compared with control. Immunofluorescence and Western blot results showed that the nuclear translocation of NF-κB in the agonist-CD137 group was enhanced, and ELISA results showed that the secretion of proinflammatory cytokines in the agonist-CD137 group was increased. Immunofluorescence results revealed that ROS production in the agonist-CD137 group was higher than that in control, M5580 (a Nrf2 pathway agonist) and CAPE (a NF-κB pathway inhibitor) groups. In vitro studies using HUVECs and in vivo studies using high-fat-fed ApoE−/− mice showed that the number of apoptotic endothelial cells was the highest in the agonist-CD137 group. By contrast, both M5580 and CAPE treatments were able to reduce CD137 induced ECs apoptosis. Conclusions Our results showed that CD137 signaling promotes ECs apoptosis through prooxidative and proinflammatory mechanisms, mediated by Nrf2 and NF-κB pathways, respectively.
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Wong HY, Schwarz H. CD137 / CD137 ligand signalling regulates the immune balance: A potential target for novel immunotherapy of autoimmune diseases. J Autoimmun 2020; 112:102499. [PMID: 32505443 DOI: 10.1016/j.jaut.2020.102499] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/24/2020] [Accepted: 05/25/2020] [Indexed: 02/08/2023]
Abstract
CD137 (TNFRSF9, 4-1BB) is a potent co-stimulatory molecule of the tumour necrosis factor receptor superfamily (TNFRSF) that is expressed by activated T cells. CD137/CD137 ligand (CD137L) signalling primarily induces a potent cell-mediated immune response, while signalling of cell surface-expressed CD137L into antigen presenting cells enhances their activation, differentiation and migratory capacity. Studies have shown that bidirectional CD137/CD137L signalling plays an important role in the pathogenesis of autoimmune diseases. This review discusses the mechanisms how CD137/CD137L signalling contributes to immune deviation of helper T cell pathways in various murine models, and the potential of developing immunotherapies targeting CD137/CD137L signalling for the treatment of autoimmune diseases.
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Affiliation(s)
- Hiu Yi Wong
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117593, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore
| | - Herbert Schwarz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117593, Singapore; Immunology Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore.
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35
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Bengts S, Shamoun L, Kunath A, Appelgren D, Welander M, Björck M, Wanhainen A, Wågsäter D. Altered IL-32 Signaling in Abdominal Aortic Aneurysm. J Vasc Res 2020; 57:236-244. [PMID: 32434199 DOI: 10.1159/000507667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 04/02/2020] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION AND OBJECTIVE Interleukin (IL)-32 is a pro-inflammatory cytokine not previously studied in relation to abdominal aortic aneurysm (AAA). The aim of this study was to elucidate the expression and localization of IL-32 in AAA. METHODS Expression and localization of IL-32 in human aortic tissue was studied with immunohistochemical analysis and Western blot (AAA: n = 5; controls: n = 4). ELISA was used to measure IL-32 in human plasma samples (AAA: n = 140; controls: n = 37) and in media from cultured peripheral blood mononuclear cells (PBMCs) from 3 healthy donors. IL-32 mRNA in PBMCs, endothelial cells, aortic smooth muscle cells (SMCs), and aortic tissue samples of AAA (n = 16) and control aortas (n = 9) was measured with qPCR. RESULTS IL-32 was predominantly expressed in SMCs and T-cell-rich areas. Highest mRNA expression was observed in the intima/media layer of the AAA. A weaker protein expression was detected in non-aneurysmal aortas. Expression of IL-32 was confirmed in isolated T cells, macrophages, endothelial cells, and SMCs, where expression was also inducible by cytokines such as interferon-γ. There was no difference in IL-32 expression in plasma between patients and controls. CONCLUSION IL-32 signaling is altered locally in AAA and could potentially play an important role in aneurysm development. Further studies using animal models would be helpful to study its potential role in AAA disease.
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Affiliation(s)
- Sophy Bengts
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Levar Shamoun
- Division of Medical Diagnostics, Department of Laboratory Medicine, Jönköping County, Jönköping, Sweden.,Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Anne Kunath
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Daniel Appelgren
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Martin Welander
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Martin Björck
- Department of Surgical Sciences, Section of Vascular Surgery, Uppsala University, Uppsala, Sweden
| | - Anders Wanhainen
- Department of Surgical Sciences, Section of Vascular Surgery, Uppsala University, Uppsala, Sweden
| | - Dick Wågsäter
- Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden, .,Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden,
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Xu J, Yang Y. Potential genes and pathways along with immune cells infiltration in the progression of atherosclerosis identified via microarray gene expression dataset re-analysis. Vascular 2020; 28:643-654. [PMID: 32379583 DOI: 10.1177/1708538120922700] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Atherosclerosis is a chronic inflammatory process characterized by the accumulation and formation of lipid-rich plaques within the layers of the arterial wall. Although numerous studies have reported the underlying pathogenesis, no data-based studies have been conducted to analyze the potential genes and immune cells infiltration in the different stages of atherosclerosis via bioinformatics analysis. METHODS In this study, we downloaded GSE100927 and GSE28829 from NCBI-GEO database. Gene ontology and pathway enrichment were performed via the DAVID database. The protein interaction network was constructed via STRING. Enriched hub genes were analyzed by the Cytoscape software. The evaluation of the infiltrating immune cells in the dataset samples was performed by the CIBERSORT algorithm. RESULTS We identified 114 common upregulated differentially expressed genes and 22 common downregulated differentially expressed genes. (adjust p value < 0.01 and log FC ≥ 1). A cluster of 10 genes including CYBA, SLC11A1, FCER1G, ITGAM, ITGB2, CD53, ITGAX, VAMP8, CLEC5A, and CD300A were found to be significant. Through the deconvolution algorithm CIBERSORT, we analyzed the significant alteration of immune cells infiltration in the progression of atherosclerosis with the threshold of the Wilcoxon test at p value <0.05. CONCLUSIONS These results may reveal the underlying correlations between genes and immune cells in atherosclerosis, which enable us to investigate the novel insights for the development of treatments and drugs.
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Affiliation(s)
- Jing Xu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Beijing, China.,Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yuejin Yang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Beijing, China.,Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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Narverud I, Christensen JJ, Bakke SS, Ulven SM, Rundblad A, Aukrust P, Espevik T, Bogsrud MP, Retterstøl K, Ueland T, Halvorsen B, Holven KB. Profiling of immune-related gene expression in children with familial hypercholesterolaemia. J Intern Med 2020; 287:310-321. [PMID: 31631426 DOI: 10.1111/joim.13001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Innate and adaptive immune responses are pivotal in atherosclerosis, but their association with early-stage atherosclerosis in humans is incompletely understood. In this regard, untreated children with familial hypercholesterolaemia may serve as a human model to investigate the effect of elevated low-density lipoprotein (LDL)-cholesterol. OBJECTIVES We aimed to study the immunological and inflammatory pathways involved in early atherosclerosis by examining mRNA molecules in peripheral blood mononuclear cells (PBMCs) from children with FH. METHODS We analysed the level of 587 immune-related mRNA molecules using state-of-the-art Nanostring technology in PBMCs from children with (n = 30) and without (n = 21) FH, and from FH children before and after statin therapy (n = 10). RESULTS 176 genes (30%) were differentially expressed between the FH and healthy children at P < 0.05. Compared to healthy children, the dysregulated pathways in FH children included the following: T cells (18/19); B cells (5/6); tumour necrosis factor super family (TNFSF) (6/8); cell growth, proliferation and differentiation (5/7); interleukins (5/9); toll-like receptors (2/5); apoptosis (3/7) and antigen presentation (1/7), where the ratio denotes higher expressed genes to total number of genes. Statin therapy reversed expression of thirteen of these mRNAs in FH children. CONCLUSION FH children display higher PBMC expression of immune-related genes mapped to several pathways, including T and B cells, and TNFSF than healthy children. Our results suggest that LDL-C plays an important role in modulating expression of different immune-related genes, and novel data on the involvement of these pathways in the early atherosclerosis may represent future therapeutic targets for prevention of atherosclerotic progression.
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Affiliation(s)
- I Narverud
- Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.,Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - J J Christensen
- Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.,Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - S S Bakke
- Center of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - S M Ulven
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - A Rundblad
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - P Aukrust
- Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Oslo, Norway
| | - T Espevik
- Center of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - M P Bogsrud
- Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.,Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital, Oslo, Norway
| | - K Retterstøl
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.,The Lipid Clinic, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - T Ueland
- Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,K.G. Jebsen TREC, The Faculty of Health Sciences, The Arctic University of Tromsø, Tromsø, Norway
| | - B Halvorsen
- Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - K B Holven
- Norwegian National Advisory Unit on Familial Hypercholesterolemia, Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.,Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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Xu Y, Yan Y, Geng T, Wang C, Xu Y, Yang P, Yan J. CD137-CD137L Signaling Affects Angiogenesis by Mediating Phenotypic Conversion of Macrophages. J Cardiovasc Pharmacol 2020; 75:148-154. [DOI: 10.1097/fjc.0000000000000772] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Abstract
The role of inflammation in cardiovascular disease (CVD) is now widely accepted. Immune cells, including T cells, are influenced by inflammatory signals and contribute to the onset and progression of CVD. T cell activation is modulated by T cell co-stimulation and co-inhibition pathways. Immune checkpoint inhibitors (ICIs) targeting T cell inhibition pathways have revolutionized cancer treatment and improved survival in patients with cancer. However, ICIs might induce cardiovascular toxicity via T cell re-invigoration. With the rising use of ICIs for cancer treatment, a timely overview of the role of T cell co-stimulation and inhibition molecules in CVD is desirable. In this Review, the importance of these molecules in the pathogenesis of CVD is highlighted in preclinical studies on models of CVD such as vein graft disease, myocarditis, graft arterial disease, post-ischaemic neovascularization and atherosclerosis. This Review also discusses the therapeutic potential of targeting T cell co-stimulation and inhibition pathways to treat CVD, as well as the possible cardiovascular benefits and adverse events after treatment. Finally, the Review emphasizes that patients with cancer who are treated with ICIs should be monitored for CVD given the reported association between the use of ICIs and the risk of cardiovascular toxicity.
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Activation of CD137 signaling promotes neointimal formation by attenuating TET2 and transferrring from endothelial cell-derived exosomes to vascular smooth muscle cells. Biomed Pharmacother 2020; 121:109593. [DOI: 10.1016/j.biopha.2019.109593] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 10/22/2019] [Accepted: 10/26/2019] [Indexed: 12/12/2022] Open
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Herrero-Fernandez B, Gomez-Bris R, Somovilla-Crespo B, Gonzalez-Granado JM. Immunobiology of Atherosclerosis: A Complex Net of Interactions. Int J Mol Sci 2019; 20:E5293. [PMID: 31653058 PMCID: PMC6862594 DOI: 10.3390/ijms20215293] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease is the leading cause of mortality worldwide, and atherosclerosis the principal factor underlying cardiovascular events. Atherosclerosis is a chronic inflammatory disease characterized by endothelial dysfunction, intimal lipid deposition, smooth muscle cell proliferation, cell apoptosis and necrosis, and local and systemic inflammation, involving key contributions to from innate and adaptive immunity. The balance between proatherogenic inflammatory and atheroprotective anti-inflammatory responses is modulated by a complex network of interactions among vascular components and immune cells, including monocytes, macrophages, dendritic cells, and T, B, and foam cells; these interactions modulate the further progression and stability of the atherosclerotic lesion. In this review, we take a global perspective on existing knowledge about the pathogenesis of immune responses in the atherosclerotic microenvironment and the interplay between the major innate and adaptive immune factors in atherosclerosis. Studies such as this are the basis for the development of new therapies against atherosclerosis.
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Affiliation(s)
- Beatriz Herrero-Fernandez
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
- Departamento de Fisiología. Facultad de Medicina. Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
| | - Raquel Gomez-Bris
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
| | | | - Jose Maria Gonzalez-Granado
- LamImSys Lab. Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain.
- Departamento de Fisiología. Facultad de Medicina. Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain.
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Kusters PJH, Lutgens E, Seijkens TTP. Exploring immune checkpoints as potential therapeutic targets in atherosclerosis. Cardiovasc Res 2019; 114:368-377. [PMID: 29309533 DOI: 10.1093/cvr/cvx248] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 12/21/2017] [Indexed: 12/20/2022] Open
Abstract
In the past decades, the inflammatory nature of atherosclerosis has been well-recognized and despite the development of therapeutic strategies targeted at its classical risk factors such as dyslipidemia and hypertension, atherosclerosis remains a major cause of morbidity and mortality. Additional strategies targeting the chronic inflammatory pathways underlying the development of atherosclerosis are therefore required. Interactions between different immune cells result in the secretion of inflammatory mediators, such as cytokines and chemokines, and fuel atherogenesis. Immune checkpoint proteins have a critical role in facilitating immune cell interactions and play an essential role in the development of atherosclerosis. Although the therapeutic potential of these molecules is well-recognized in clinical oncology, the use of immune checkpoint modulators in atherosclerosis is still limited to experimental models. Here, we review recent insights on the role of immune checkpoint proteins in atherosclerosis. Additionally, we explore the therapeutic potential and challenges of immune checkpoint modulating strategies in cardiovascular medicine and we discuss novel therapeutic approaches to target these proteins in atherosclerosis.
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Affiliation(s)
- Pascal J H Kusters
- Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 15, 1105 CZ Amsterdam, The Netherlands
| | - Esther Lutgens
- Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 15, 1105 CZ Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University (LMU), Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Tom T P Seijkens
- Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center (AMC), University of Amsterdam, Meibergdreef 15, 1105 CZ Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University (LMU), Pettenkoferstraße 8a, 80336 Munich, Germany
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Xu MM, Murphy PA, Vella AT. Activated T-effector seeds: cultivating atherosclerotic plaque through alternative activation. Am J Physiol Heart Circ Physiol 2019; 316:H1354-H1365. [PMID: 30925075 PMCID: PMC6620674 DOI: 10.1152/ajpheart.00148.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 03/21/2019] [Accepted: 03/25/2019] [Indexed: 02/07/2023]
Abstract
Atherosclerosis is a chronic inflammatory pathology that precipitates substantial morbidity and mortality. Although initiated by physiological patterns of low and disturbed flow that differentially prime endothelial cells at sites of vessel branch points and curvature, the chronic, smoldering inflammation of atherosclerosis is accelerated by comorbidities involving inappropriate activation of the adaptive immune system, such as autoimmunity. The innate contributions to atherosclerosis, especially in the transition of monocyte to lipid-laden macrophage, are well established, but the mechanisms underpinning the infiltration, persistence, and effector dynamics of CD8 T cells in particular are not well understood. Adaptive immunity is centered on a classical cascade of antigen recognition and activation, costimulation, and effector cytokine secretion upon recall of antigen. However, chronic inflammation can generate alternative cues that supplant this behavior pattern and promote the retention and activation of peripherally activated T cells. Furthermore, the atherogenic foci that activated immune cell infiltrate are unique lipid-laden environments that offer a diverse array of stimuli, including those of survival, antigen hyporesponsiveness, and inflammatory cytokine expression. This review will focus on how known cardiovascular comorbidities may be influencing CD8 T-cell activation and how, once infiltrated within atherogenic foci, these T cells face a multitude of cues that skew the classical cascade of T-cell behavior, highlighting alternative modes of activation that may help contextualize associations of autoimmunity, viral infection, and immunotherapy with cardiovascular morbidity.
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Affiliation(s)
- Maria M Xu
- Department of Immunology, School of Medicine, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Patrick A Murphy
- Center for Vascular Biology, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Anthony T Vella
- Department of Immunology, School of Medicine, University of Connecticut Health School of Medicine , Farmington, Connecticut
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Lack of association of tumor necrosis factor superfamily member 4 (TNFSF4) gene polymorphisms (rs3850641 and rs17568) with coronary heart disease and stroke: A systematic review and meta-analysis. Anatol J Cardiol 2019; 19:86-93. [PMID: 29424751 PMCID: PMC5864823 DOI: 10.14744/anatoljcardiol.2017.8069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Objective: To evaluate the association between the tumor necrosis factor superfamily member 4 (TNFSF4) gene polymorphisms and common cardiovascular and cerebrovascular diseases. Methods: A literature-based search was conducted through databases including PubMed, EMBASE, Cochrane Library, CNKI, and WanFang data. Crude odds ratios (ORs) and 95% confidence intervals (CI) were calculated to estimate the strength of the association between TNFSF4 polymorphisms (rs3850641 and rs17568) and the risk of coronary heart disease (CHD) and stroke. Results: Overall, 11 eligible studies were included in this meta-analysis. G allele was showed not to be associated with CHD and stroke, compared with A allele (rs3850641: OR=1.02, 95% CI=0.89–1.17; rs17568: OR=1.09, 95% CI=0.89–1.33). Genotypic analysis demonstrated that there was no significant association between the risk of CHD and stroke and rs3850641 [homozygous comparison (GG vs. AA): OR=1.05, 95% CI=0.74–1.50; heterozygous comparison (GA vs. AA): OR=1.00, 95% CI=0.88–1.13; recessive model (GG vs. GA+AA): OR=1.04, 95% CI=0.76–1.43; dominant model (GG+GA vs. AA): OR=1.01, 95% CI=0.88–1.17]. Similarly, no susceptibility between CHD and stroke and rs17568 polymorphism was uncovered (GG vs. AA: OR=1.04, 95% CI=0.74–1.46; GA vs. AA: OR=1.07, 95% CI=0.62–1.83; GG+GA vs. AA: OR=1.13, 95% CI=0.82–1.56; GG vs. GA+AA: OR=1.01, 95% CI=0.74–1.39). Conclusion: The present study demonstrated that there is no significant relationship between TNFSF4 gene polymorphism and cerebrovascular and cardiovascular diseases.
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Xu MM, Ménoret A, Nicholas SAE, Günther S, Sundberg EJ, Zhou B, Rodriguez A, Murphy PA, Vella AT. Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci. Am J Physiol Heart Circ Physiol 2019; 316:H1480-H1494. [PMID: 30978132 DOI: 10.1152/ajpheart.00088.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well understood. CD137 (4-1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen primed and CD137 costimulated. We analyzed atherogenic LDF vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T-cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF vessels and promotes a persistent innate-like proinflammatory program. Residence of CD137+ effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, whereas CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci. NEW & NOTEWORTHY Our studies identify CD137 costimulation as a stimulus for effector CD8 T-cell infiltration and persistence within atherogenic foci, regardless of atherosclerotic-antigen recognition. These costimulated effector cells, which are generated in pathological states such as viral infection and autoimmunity, have innate-like proinflammatory programs in circulation and within the atherosclerotic microenvironment, providing mechanistic context for clinical correlations of cardiovascular morbidity with increased CD8 T-cell infiltration and markers of activation in the absence of established antigen specificity.
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Affiliation(s)
- Maria M Xu
- Department of Immunology, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Antoine Ménoret
- Department of Immunology, University of Connecticut Health School of Medicine , Farmington, Connecticut.,Institute for Systems Genomics, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Sarah-Anne E Nicholas
- Center for Vascular Biology, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Sebastian Günther
- Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland
| | - Eric J Sundberg
- Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.,Department of Medicine, University of Maryland School of Medicine , Baltimore, Maryland.,Department of Microbiology and Immunology, University of Maryland School of Medicine , Baltimore, Maryland
| | - Beiyan Zhou
- Department of Immunology, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Annabelle Rodriguez
- Center for Vascular Biology, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Patrick A Murphy
- Center for Vascular Biology, University of Connecticut Health School of Medicine , Farmington, Connecticut
| | - Anthony T Vella
- Department of Immunology, University of Connecticut Health School of Medicine , Farmington, Connecticut
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Li XQ, Wang YY, Yang TT, Qian YN, Yin H, Zhong SS, A R, He Y, Xu BL, Liu GZ. Increased Peripheral CD137 Expression in a Mouse Model of Permanent Focal Cerebral Ischemia. Cell Mol Neurobiol 2019; 39:451-460. [PMID: 30778712 PMCID: PMC11469804 DOI: 10.1007/s10571-019-00661-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 02/07/2019] [Indexed: 11/30/2022]
Abstract
Various studies demonstrate that CD137 (TNFRSF9, 4-1BB) promotes atherosclerosis and vascular inflammation in experimental models via interactions with the CD137 ligand (CD137L). However, the exact role of CD137 in ischemic stroke remains unclear. In this study, we analyzed dynamic changes of peripheral CD137 expression on T cells in a mouse model of cerebral ischemia-middle cerebral artery occlusion (MCAO), as well as alternation of neurological function, infarct size and cerebral inflammatory status after inhibition of the CD137/CD137L pathway using an anti-CD137L monoclonal antibody. MCAO mice showed elevated surface expression of CD137 on T cells in both peripheral blood and lymphoid tissues during early cerebral ischemia. Remarkably, blockade of the CD137/CD137L pathway reduced the post-ischemic brain damage. Our findings indicate that enhanced CD137 costimulation occurs in early cerebral ischemia and promotes T cell activation, which in turn upregulates inflammatory immune response and possibly exerting deleterious effects on cerebral ischemia.
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Affiliation(s)
- Xiao-Qing Li
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Yang-Yang Wang
- Department of Neurology, Peking University People's Hospital, Beijing, 100044, China
| | - Ting-Ting Yang
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Yi-Ning Qian
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - He Yin
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Shan-Shan Zhong
- Department of Neurology, Peking University People's Hospital, Beijing, 100044, China
| | - Rong A
- Department of Neurology, Peking University People's Hospital, Beijing, 100044, China
| | - Yang He
- Department of Neurology, Peking University People's Hospital, Beijing, 100044, China
| | - Bao-Lei Xu
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China
| | - Guang-Zhi Liu
- Department of Neurology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
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The expression and clinical correlations of 4-1BB on peripheral CD4+ T cell subsets in patients with coronary artery disease. A cross-sectional pilot study. Clin Chim Acta 2018; 487:341-348. [PMID: 30359586 DOI: 10.1016/j.cca.2018.10.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 09/14/2018] [Accepted: 10/21/2018] [Indexed: 11/21/2022]
Abstract
BACKGROUND The expression of 4-1BB on peripheral regulatory T cells (Tregs) and conventional T cells (Tconvs) in coronary artery disease (CAD) patients is unknown. We aimed to investigate the expression and clinical correlations of 4-1BB on peripheral Tregs and Tconvs in CAD patients. METHODS Flow cytometry analysis was used to analyze 4-1BB expression on peripheral Tregs and Tconvs. We compared the percentages of 4-1BB on Tregs and Tconvs in the control (ctrl) group, the stable ischemic heart disease (SIHD) group, and the acute coronary syndrome (ACS) group. The correlations of 4-1BB expression on Tregs and Tconvs with the Gensini score and CRP were examined in the ACS group. The value of 4-1BB percentage on Tregs for predicting CAD in this cardiovascular risk population was also analyzed. RESULTS A total of 71 participants were enrolled in this study. In all the groups, the percentages of 4-1BB on Tregs were significantly higher than on Tconvs (all P < .05). After adjusting for sex, age, SBP, HbA1c and LDL, 4-1BB percentages on Tregs and Tconvs were significantly higher in the SIHD and ACS groups compared with the ctrl group (all P < .05). The ratio of 4-1BB percentage on Tregs to 4-1BB percentage on Tconvs was higher in the ACS group compared with the ctrl group (P = .010). In the ACS group, CRP was negatively correlated with the Tregs percentage (in CD4+ T cells) and the Tregs percentage to Tconvs percentage ratio. The Gensini score was positively correlated with the 4-1BB percentage on Tregs in the ACS group. Linear regression analysis showed 4-1BB percentage on Tregs independently predicted the Gensini score. Binary logistic regression showed CRP, HbA1c and 4-1BB percentage on Tregs independently predicted the development of CAD (SIHD+ACS) in the whole population. CONCLUSION 4-1BB expression on peripheral Tregs and Tconvs was increased in SIHD and ACS patients. 4-1BB percentage on Tregs positively correlated with the severity of coronary artery stenosis in ACS patients. 4-1BB percentage on Tregs independently predicted the severity of coronary artery stenosis in an ACS population and development of CAD in a cardiovascular risk population.
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Hypermethylation of the Micro-RNA 145 Promoter Is the Key Regulator for NLRP3 Inflammasome-Induced Activation and Plaque Formation. JACC Basic Transl Sci 2018; 3:604-624. [PMID: 30456333 PMCID: PMC6234615 DOI: 10.1016/j.jacbts.2018.06.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 05/14/2018] [Accepted: 06/19/2018] [Indexed: 01/17/2023]
Abstract
miR-145 in vessels decreases with plaque progression. DNMT1 and TET2 dynamic imbalance leads to miR-145 promoter hypermethylation. Reduction of miR-145 activates NLRP3 inflammasome through CD137/NFATc1 signaling. DNMT1 and TET2 could be promising therapeutic candidates for atherosclerosis in the future. Two major issues are involved in clinical atherosclerosis treatment. First, there are no significant clinical markers for early diagnosis of atherosclerosis. Second, the plaque will not regress once it initiates even if the risk factors are removed. In this paper, the research shows that the hypermethylation level of the microRNA 145 (miR-145) promoter is related to a DNMT1 and TET2 dynamic imbalance. The reduction of miR-145 causes NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome activation through CD137/NFATc1 signaling. These findings could be a potential target for plaque regression in the future.
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Activation of CD137 Signaling Enhances Vascular Calcification through c-Jun N-Terminal Kinase-Dependent Disruption of Autophagic Flux. Mediators Inflamm 2018; 2018:8407137. [PMID: 30356425 PMCID: PMC6178178 DOI: 10.1155/2018/8407137] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 06/25/2018] [Accepted: 07/16/2018] [Indexed: 01/17/2023] Open
Abstract
Background Vascular calcification is widespread and clinically significant, contributing to substantial morbidity and mortality. Calcifying vascular cells are partly derived from local vascular smooth muscle cells (VSMCs), which can undergo chondrogenic or osteogenic differentiation under inflammatory environment. Recently, we have found activation of CD137 signaling accelerated vascular calcification. However, the underlying mechanism remains unknown. This study aims to identify key mediators involved in CD137 signaling-induced vascular calcification in vivo and in vitro. Methods Autophagy flux was measured through mRFP-GFP-LC3 adenovirus and transmission electron microscopy. Von Kossa assay and alkaline phosphatase (ALP) activity were used to observe calcification in vivo and in vitro, respectively. Autophagosome-containing vesicles were collected and identified by flow cytometry and Western blot. Autophagy or calcification-associated targets were measured by Western blot, quantitative real-time PCR, and immunohistochemistry. Results Treatment with the agonist-CD137 displayed c-Jun N-terminal kinase- (JNK-) dependent increase in the expression of various markers of autophagy and the number of autophagosomes relative to the control group. Autophagy flux experiments suggested that agonist-CD137 blocked the fusion of autophagosomes with lysosomes in cultured VSMCs. Calcium deposition, ALP activity, and the expression of calcification-associated proteins also increased in agonist-CD137 group compared with anti-CD137 group, which could be recovered by autophagy stimulator rapamycin. Autophagosome-containing vesicles collected from agonist-CD137 VSMCs supernatant promoted VSMC calcification. Conclusion The present study identified a new pathway in which CD137 promotes VSMC calcification through the activation of JNK signaling, subsequently leading to the disruption of autophagic flux, which is responsible for CD137-induced acceleration of vascular calcification.
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Abstract
Innate and adaptive immune effector mechanisms, in conjunction with hyperlipidemia, are important drivers of atherosclerosis. The interaction between the different immune cells and the secretion of cytokines and chemokines determine the progression of atherosclerosis. The activation or dampening of the immune response is tightly controlled by immune checkpoints. Costimulatory and coinhibitory immune checkpoints represent potential targets for immune modulatory therapies for atherosclerosis. This review will discuss the current knowledge on immune checkpoints in atherosclerosis and the clinical potential of immune checkpoint targeted therapy for atherosclerosis.
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Affiliation(s)
- Ellen Rouwet
- From the Department of Surgery and Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (E.R.)
| | - Esther Lutgens
- Department of Medical Biochemistry, Experimental Vascular Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands (E.L.)
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian's University (LMU), Munich, Germany (E.L.)
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