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1
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Liu X, Gutierrez Jauregui R, Lueder Y, Halle S, Ospina-Quintero L, Ritter C, Schimrock A, Willenzon S, Janssen A, Wagner K, Messerle M, Bošnjak B, Förster R. Protective function of ex vivo-expanded CD8 T cells in a mouse model of adoptive therapy for cytomegalovirus infection depends on integrin beta 1 but not CXCR3, CTLA4, or PD-1 expression. J Leukoc Biol 2025; 117:qiae256. [PMID: 40276928 DOI: 10.1093/jleuko/qiae256] [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: 08/20/2024] [Revised: 10/24/2024] [Indexed: 04/26/2025] Open
Abstract
The adoptive transfer of virus-specific T cells (VSTs) represents a therapeutic option for viral infection treatment in immunocompromised patients. Before administration, ex vivo culture enables VST expansion. However, it is unclear how ex vivo expansion affects the circulation, homing, and intra-tissue migration of administered VSTs. We established a model of VST immunotherapy of acute cytomegalovirus infection using adoptive transfer of ex vivo-expanded OT-I CD8 T cells (recognizing SIINFEKL peptide) into Rag2-/- mice infected with murine cytomegalovirus (MCMV) encoding for the SIINFEKL peptide. Ex vivo expansion induced an effector T cell phenotype and affected the expression of integrins and chemokine receptors. CRISPR/Cas9-mediated gene deletions enabled us to address the role of selected genes in the homing of VSTs following intravenous administration. We found that deletion of Itgb1, encoding for integrin beta 1, prevented OT-I cells from entering infected organs and drastically reduced their number in blood, suggesting that adoptively transferred VSTs primarily expand in the infected tissues. By contrast, Cxcr3-/- OT-I cells provided equal protection as their Cxcr3+/+ counterparts, indicating that this chemokine receptor does not contribute to VST entry into infected organs. Further, Pdcd1 and Ctla4 deletion did not impair the transferred OT-I cells' ability to protect mice from MCMV, arguing against quick exhaustion of VSTs with an effector T cell phenotype. Together, these data indicate that ex vivo expansion affects migration and activation properties of VSTs and suggest that future clinical evaluation of adoptive T cell therapy efficacy should include homing molecule expression assessment.
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Affiliation(s)
- Xiaokun Liu
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | | | - Yvonne Lueder
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Stephan Halle
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Laura Ospina-Quintero
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Christiane Ritter
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Anja Schimrock
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Stefanie Willenzon
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Anika Janssen
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Karen Wagner
- Institute of Virology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Martin Messerle
- Institute of Virology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Berislav Bošnjak
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
| | - Reinhold Förster
- Institute of Immunology, Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, Hannover 30625, Germany
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2
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Harkness T, Wilkinson K, Loo YK, Howard VJ, Cushman M, Zakai NA, Cheung KL, Judd SE, Plante TB. Cell adhesion molecules and incident hypertension in black and white adults: the REGARDS study. J Hypertens 2025:00004872-990000000-00657. [PMID: 40156350 DOI: 10.1097/hjh.0000000000004004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 02/26/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND Higher C-reactive protein-quantified inflammation associates with greater incident hypertension risk. E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) are cell adhesion molecules that aid leukocyte adhesion during inflammation. Their association with incident hypertension is unclear. METHODS REGARDS enrolled 30 239 Black and White US adults aged ≥45 years from across the contiguous United States in 2003-2007, with a second exam in 2013-2016. The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study included 4400 REGARDS participants who attended both exams. We excluded participants with hypertension or missing biomarkers at baseline. Hypertension used a 140/90 mmHg threshold or self-reported use of blood pressure (BP) lowering medications. Modified Poisson regression estimated relative risk (RR) of incident hypertension by tertile of baseline E-Selectin, ICAM-1, and VCAM-1. RESULTS Among 1879 nonhypertensive participants (mean [SD] age 62 [8] years, 25% Black race, 55% women) with 9 years median follow up, 36% developed hypertension. E-selectin and ICAM-1 were higher among Black participants; VCAM-1 was higher among White participants. Higher E-selectin was associated with greater risk of incident hypertension among White but not Black adults in some models (e.g., minimally adjusted: RR 1.27; 95% confidence interval (CI) 1.04-1.44 comparing tertile 3 vs. 1) ICAM-1 was associated with greater hypertension risk in only an unadjusted model. CONCLUSION In a prospective study of Black and White US adults, E-selectin was associated with incident hypertension among White adults and ICAM-1 in White and Black adults in partially or unadjusted models. Modification of E-selectin might be tested to lower risk of hypertension development.
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Affiliation(s)
| | - Katherine Wilkinson
- Larner College of Medicine at the University of Vermont, Burlington, Vermont
| | - Ying K Loo
- Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts
| | | | - Mary Cushman
- Larner College of Medicine at the University of Vermont, Burlington, Vermont
| | - Neil A Zakai
- Larner College of Medicine at the University of Vermont, Burlington, Vermont
| | - Katharine L Cheung
- Larner College of Medicine at the University of Vermont, Burlington, Vermont
| | - Suzanne E Judd
- University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Timothy B Plante
- Larner College of Medicine at the University of Vermont, Burlington, Vermont
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3
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Feng X, Cao F, Wu X, Xie W, Wang P, Jiang H. Targeting extracellular matrix stiffness for cancer therapy. Front Immunol 2024; 15:1467602. [PMID: 39697341 PMCID: PMC11653020 DOI: 10.3389/fimmu.2024.1467602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 11/06/2024] [Indexed: 12/20/2024] Open
Abstract
The physical characteristics of the tumor microenvironment (TME) include solid stress, interstitial fluid pressure, tissue stiffness and microarchitecture. Among them, abnormal changes in tissue stiffness hinder drug delivery, inhibit infiltration of immune killer cells to the tumor site, and contribute to tumor resistance to immunotherapy. Therefore, targeting tissue stiffness to increase the infiltration of drugs and immune cells can offer a powerful support and opportunities to improve the immunotherapy efficacy in solid tumors. In this review, we discuss the mechanical properties of tumors, the impact of a stiff TME on tumor cells and immune cells, and the strategies to modulate tumor mechanics.
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Affiliation(s)
- Xiuqin Feng
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fujun Cao
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiangji Wu
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wenyan Xie
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ping Wang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hong Jiang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Magnusen AF, Pandey MK. Complement System and Adhesion Molecule Skirmishes in Fabry Disease: Insights into Pathogenesis and Disease Mechanisms. Int J Mol Sci 2024; 25:12252. [PMID: 39596318 PMCID: PMC11594573 DOI: 10.3390/ijms252212252] [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: 09/12/2024] [Revised: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase alpha (GLA) gene, resulting in the accumulation of globotriaosylceramide (Gb3) and its deacetylated form, globotriaosylsphingosine (Lyso-Gb3) in various tissues and fluids throughout the body. This pathological accumulation triggers a cascade of processes involving immune dysregulation and complement system activation. Elevated levels of complement 3a (C3a), C5a, and their precursor C3 are observed in the plasma, serum, and tissues of patients with Fabry disease, correlating with significant endothelial cell abnormalities and vascular dysfunction. This review elucidates how the complement system, particularly through the activation of C3a and C5a, exacerbates disease pathology. The activation of these pathways leads to the upregulation of adhesion molecules, including vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), platelet and endothelial cell adhesion molecule 1 (PECAM1), and complement receptor 3 (CR3) on leukocytes and endothelial cells. This upregulation promotes the excessive recruitment of leukocytes, which in turn exacerbates disease pathology. Targeting complement components C3a, C5a, or their respective receptors, C3aR (C3a receptor) and C5aR1 (C5a receptor 1), could potentially reduce inflammation, mitigate tissue damage, and improve clinical outcomes for individuals with Fabry disease.
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Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
| | - Manoj Kumar Pandey
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA;
- Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA
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Dupas A, Goetz JG, Osmani N. Extravasation of immune and tumor cells from an endothelial perspective. J Cell Sci 2024; 137:jcs262066. [PMID: 39530179 DOI: 10.1242/jcs.262066] [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: 11/16/2024] Open
Abstract
Crossing the vascular endothelium is a necessary stage for circulating cells aiming to reach distant organs. Leukocyte passage through the endothelium, known as transmigration, is a multistep process during which immune cells adhere to the vascular wall, migrate and crawl along the endothelium until they reach their exit site. Similarly, circulating tumor cells (CTCs), which originate from the primary tumor or reseed from early metastatic sites, disseminate using the blood circulation and also must cross the endothelial barrier to set new colonies in distant organs. CTCs are thought to mimic arrest and extravasation utilized by leukocytes; however, their extravasation also requires processes that, from an endothelial perspective, are specific to cancer cells. Although leukocyte extravasation relies on maintaining endothelial impermeability, it appears that cancer cells can indoctrinate endothelial cells into promoting their extravasation independently of their normal functions. In this Review, we summarize the common and divergent mechanisms of endothelial responses during extravasation of leukocytes (in inflammation) and CTCs (in metastasis), and highlight how these might be leveraged in the development of anti-metastatic treatments.
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Affiliation(s)
- Amandine Dupas
- Tumor Biomechanics lab, INSERM UMR_S 1109, CRBS, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg Cedex, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France
- Equipe Labellisée Ligue Contre le Cancer, France
| | - Jacky G Goetz
- Tumor Biomechanics lab, INSERM UMR_S 1109, CRBS, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg Cedex, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France
- Equipe Labellisée Ligue Contre le Cancer, France
| | - Naël Osmani
- Tumor Biomechanics lab, INSERM UMR_S 1109, CRBS, 1 rue Eugène Boeckel, CS 60026, 67084 Strasbourg Cedex, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, F-67000, France
- Equipe Labellisée Ligue Contre le Cancer, France
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Januskevicius A, Vasyle E, Rimkunas A, Malakauskas K. Integrative Cross-Talk in Asthma: Unraveling the Complex Interactions Between Eosinophils, Immune, and Structural Cells in the Airway Microenvironment. Diagnostics (Basel) 2024; 14:2448. [PMID: 39518415 PMCID: PMC11545034 DOI: 10.3390/diagnostics14212448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Asthma is a chronic inflammatory process that leads to airway narrowing, causing breath loss followed by spasms, wheezing, and shortness of breath. Within the asthmatic lungs, interaction among various immune cells and structural cells plays a significant role in orchestrating an inflammatory response in which eosinophils hold central importance. In these settings, allergens or other environmental exposures commonly drive the immune response to recruit eosinophils to the airways. The appearance of eosinophils in the airways indicates a dynamic interplay of various cell types within lung tissue and does not represent a passive effect of inflammation. The cellular cross-talk causes the persistence of eosinophilic inflammation, and if left untreated, it results in long-term damage to the airway structure and function. Further exacerbation of the condition occurs because of this. We discuss how this complex interplay of eosinophils, immune, and structural cells within the airway microenvironment leads to the distinct pathophysiological features in asthma, the variability in disease severity, and the response to biological treatments.
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Affiliation(s)
- Andrius Januskevicius
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
| | - Egle Vasyle
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
| | - Airidas Rimkunas
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
| | - Kestutis Malakauskas
- Laboratory of Pulmonology, Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.V.); (A.R.); (K.M.)
- Department of Pulmonology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania
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7
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Mastrogiovanni M, Donnadieu E, Pathak R, Di Bartolo V. Subverting Attachment to Prevent Attacking: Alteration of Effector Immune Cell Migration and Adhesion as a Key Mechanism of Tumor Immune Evasion. BIOLOGY 2024; 13:860. [PMID: 39596815 PMCID: PMC11591779 DOI: 10.3390/biology13110860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/19/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024]
Abstract
Cell adhesion regulates specific migratory patterns, location, communication with other cells, physical interactions with the extracellular matrix, and the establishment of effector programs. Proper immune control of cancer strongly depends on all these events occurring in a highly accurate spatiotemporal sequence. In response to cancer-associated inflammatory signals, effector immune cells navigating the bloodstream shift from their patrolling exploratory migration mode to establish adhesive interactions with vascular endothelial cells. This interaction enables them to extravasate through the blood vessel walls and access the cancer site. Further adhesive interactions within the tumor microenvironment (TME) are crucial for coordinating their distribution in situ and for mounting an effective anti-tumor immune response. In this review, we examine how alterations of adhesion cues in the tumor context favor tumor escape by affecting effector immune cell infiltration and trafficking within the TME. We discuss the mechanisms by which tumors directly modulate immune cell adhesion and migration patterns to affect anti-tumor immunity and favor tumor evasion. We also explore indirect immune escape mechanisms that involve modifications of TME characteristics, such as vascularization, immunogenicity, and structural topography. Finally, we highlight the significance of these aspects in designing more effective drug treatments and cellular immunotherapies.
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Affiliation(s)
- Marta Mastrogiovanni
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Emmanuel Donnadieu
- Equipe Labellisée Ligue Contre le Cancer, CNRS, INSERM, Institut Cochin, Université Paris Cité, F-75014 Paris, France;
| | - Rajiv Pathak
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Vincenzo Di Bartolo
- Immunoregulation Unit, Institut Pasteur, Université Paris Cité, F-75015 Paris, France;
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Chen J, Qin M, Xiang X, Guo X, Nie L, Mao L. Lymphocytes in autoimmune encephalitis: Pathogenesis and therapeutic target. Neurobiol Dis 2024; 200:106632. [PMID: 39117118 DOI: 10.1016/j.nbd.2024.106632] [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: 05/18/2024] [Revised: 08/04/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024] Open
Abstract
Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system characterized by the production of various autoimmune antibodies targeting neuronal proteins. The pathogenesis of AE remains elusive. Accumulating evidence suggests that lymphocytes, particularly B and T lymphocytes, play an integral role in the development of AE. In the last two decades, autoimmune neural antibodies have taken center stage in diagnosing AE. Recently, increasing evidence has highlighted the importance of T lymphocytes in the onset of AE. CD4+ T cells are thought to influence disease progression by secreting associated cytokines, whereas CD8+ T cells exert a cytotoxic role, causing irreversible damage to neurons mainly in patients with paraneoplastic AE. Conventionally, the first-line treatments for AE include intravenous steroids, intravenous immunoglobulin, and plasma exchange to remove pathogenic autoantibodies. However, a minority of patients are insensitive to conventional first-line treatment protocols and suffer from disease relapse, a condition referred to as refractory AE. In recent years, new treatments, such as rituximab or CAAR-T, which target pathogenic lymphocytes in patients with AE, have offered new therapeutic options for refractory AE. This review aims to describe the current knowledge about the function of B and T lymphocytes in the pathophysiology of AE and to summarize and update the immunotherapy options for treating this disease.
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Affiliation(s)
- Jiaojiao Chen
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengting Qin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuying Xiang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoqing Guo
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lei Nie
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ling Mao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Natarajan N, Florentin J, Johny E, Xiao H, O'Neil SP, Lei L, Shen J, Ohayon L, Johnson AR, Rao K, Li X, Zhao Y, Zhang Y, Tavakoli S, Shiva S, Das J, Dutta P. Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis. Nat Commun 2024; 15:7337. [PMID: 39187565 PMCID: PMC11347661 DOI: 10.1038/s41467-024-51780-1] [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: 09/22/2023] [Accepted: 08/16/2024] [Indexed: 08/28/2024] Open
Abstract
There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
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Affiliation(s)
- Niranjana Natarajan
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Jonathan Florentin
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Ebin Johny
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Hanxi Xiao
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
- Joint CMU-Pitt PhD program in Computational Biology, Pittsburgh, PA, USA
| | - Scott Patrick O'Neil
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Liqun Lei
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Jixing Shen
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Lee Ohayon
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Aaron R Johnson
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Krithika Rao
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Xiaoyun Li
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Yanwu Zhao
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Yingze Zhang
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Sina Tavakoli
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Sruti Shiva
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
- University of Pittsburgh School of Medicine Department of Pharmacology & Chemical Biology, Pittsburgh, PA, USA
| | - Jishnu Das
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Partha Dutta
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA.
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, USA.
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10
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Shi H, Song J, Gao L, Shan X, Panicker SR, Yao L, McDaniel M, Zhou M, McGee S, Zhong H, Griffin CT, Xia L, Shao B. Deletion of Talin1 in Myeloid Cells Facilitates Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol 2024; 44:1799-1812. [PMID: 38899470 DOI: 10.1161/atvbaha.123.319677] [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: 06/01/2023] [Accepted: 04/23/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND Integrin-regulated monocyte recruitment and cellular responses of monocyte-derived macrophages are critical for the pathogenesis of atherosclerosis. In the canonical model, talin1 controls ligand binding to integrins, a prerequisite for integrins to mediate leukocyte recruitment and induce immune responses. However, the role of talin1 in the development of atherosclerosis has not been studied. Our study investigated how talin1 in myeloid cells regulates the progression of atherosclerosis. METHODS On an Apoe-/- background, myeloid talin1-deficient mice and the control mice were fed with a high-fat diet for 8 or 12 weeks to induce atherosclerosis. The atherosclerosis development in the aorta and monocyte recruitment into atherosclerotic lesions were analyzed. RESULTS Myeloid talin1 deletion facilitated the formation of atherosclerotic lesions and macrophage deposition in lesions. Talin1 deletion abolished integrin β2-mediated adhesion of monocytes but did not impair integrin α4β1-dependent cell adhesion in a flow adhesion assay. Strikingly, talin1 deletion did not prevent Mn2+- or chemokine-induced activation of integrin α4β1 to the high-affinity state for ligands. In an in vivo competitive homing assay, monocyte infiltration into inflamed tissues was prohibited by antibodies to integrin α4β1 but was not affected by talin1 deletion or antibodies to integrin β2. Furthermore, quantitative polymerase chain reaction and ELISA (enzyme-linked immunosorbent assay) analysis showed that macrophages produced cytokines to promote inflammation and the proliferation of smooth muscle cells. Ligand binding to integrin β3 inhibited cytokine generation in macrophages, although talin1 deletion abolished the negative effects of integrin β3. CONCLUSIONS Integrin α4β1 controls monocyte recruitment during atherosclerosis. Talin1 is dispensable for integrin α4β1 activation to the high-affinity state and integrin α4β1-mediated monocyte recruitment. Yet, talin1 is required for integrin β3 to inhibit the production of inflammatory cytokines in macrophages. Thus, intact monocyte recruitment and elevated inflammatory responses cause enhanced atherosclerosis in talin1-deficient mice. Our study provides novel insights into the roles of myeloid talin1 and integrins in the progression of atherosclerosis.
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Affiliation(s)
- Huiping Shi
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center (H.S., L.X.)
| | - Jianhua Song
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Liang Gao
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Xindi Shan
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Sumith R Panicker
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Longbiao Yao
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Michael McDaniel
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Meixiang Zhou
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Samuel McGee
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Hui Zhong
- Lindsley F. Kimball Research Institute, New York Blood Center (H.Z., B.S.)
| | - Courtney T Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
| | - Lijun Xia
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center (H.S., L.X.)
| | - Bojing Shao
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (H.S., J.S., L.G., X.S., S.R.P., L.Y., M.M., M.Z., S.M., C.T.G., L.X., B.S.)
- Lindsley F. Kimball Research Institute, New York Blood Center (H.Z., B.S.)
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11
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Gao P, Liu Y, Wang X, Feng X, Liu H, Liu S, Huang X, Wu X, Xiong F, Jia X, Hui H, Jiang J, Tian J. Adhesion molecule-targeted magnetic particle imaging nanoprobe for visualization of inflammation in acute lung injury. Eur J Nucl Med Mol Imaging 2024; 51:1233-1245. [PMID: 38095676 DOI: 10.1007/s00259-023-06550-4] [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: 08/26/2023] [Accepted: 11/27/2023] [Indexed: 03/22/2024]
Abstract
PURPOSE Uncontrolled intra-alveolar inflammation is a central pathogenic feature, and its severity translates into a valid prognostic indicator of acute lung injury (ALI). Unfortunately, current clinical imaging approaches are unsuitable for visualizing and quantifying intra-alveolar inflammation. This study aimed to construct a small-sized vascular cell adhesion molecule-1 (VCAM-1)-targeted magnetic particle imaging (MPI) nanoprobe (ESPVPN) to visualize and accurately quantify intra-alveolar inflammation at the molecular level. METHODS ESPVPN was engineered by conjugating a peptide (VHPKQHRGGSK(Cy7)GC) onto a polydopamine-functionalized superparamagnetic iron oxide core. The MPI performance, targeting, and biosafety of the ESPVPN were characterized. VCAM-1 expression in HUVECs and mouse models was evaluated by western blot. The degree of inflammation and distribution of VCAM-1 in the lungs were assessed using histopathology. The expression of pro-inflammatory markers and VCAM-1 in lung tissue lysates was measured using ELISA. After intravenous administration of ESPVPN, MPI and CT imaging were used to analyze the distribution of ESPVPN in the lungs of the LPS-induced ALI models. RESULTS The small-sized (~10 nm) ESPVPN exhibited superior MPI performance compared to commercial MagImaging® and Vivotrax, and ESPVPN had effective targeting and biosafety. VCAM-1 was highly expressed in LPS-induced ALI mice. VCAM-1 expression was positively correlated with the LPS-induced dose (R = 0.9381). The in vivo MPI signal showed positive correlations with both VCAM-1 expression (R = 0.9186) and representative pro-inflammatory markers (MPO, TNF-α, IL-6, IL-8, and IL-1β, R > 0.7). CONCLUSION ESPVPN effectively targeted inflammatory lungs and combined the advantages of MPI quantitative imaging to visualize and evaluate the degree of ALI inflammation.
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Affiliation(s)
- Pengli Gao
- School of Biological Science and Medicine Engineering & School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, No. 37, Xueyuan Road, Beijing, 100191, China
- School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Yu Liu
- School of Biological Science and Medicine Engineering & School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, No. 37, Xueyuan Road, Beijing, 100191, China
- School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiaoli Wang
- School of Medical Imaging, Weifang Medical University, Weifang, 261053, China
| | - Xin Feng
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Heng Liu
- Department of Radiology, PLA Rocket Force Characteristic Medical Center, No. 16 Xinjiekou Outer Street, Beijing, 100088, China
| | - Songlu Liu
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiazi Huang
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiangjun Wu
- School of Biological Science and Medicine Engineering & School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, No. 37, Xueyuan Road, Beijing, 100191, China
- School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Fei Xiong
- School of Biological Science and Medicine Engineering & School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, No. 37, Xueyuan Road, Beijing, 100191, China
- School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Xiaohua Jia
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China
| | - Hui Hui
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China.
| | - Jingying Jiang
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, No. 37, Xueyuan Road, Beijing, 100191, China.
- School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China.
| | - Jie Tian
- Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of the People's Republic of China, No. 37, Xueyuan Road, Beijing, 100191, China.
- School of Engineering Medicine, Beihang University, No. 37, Xueyuan Road, Beijing, 100191, China.
- CAS Key Laboratory of Molecular Imaging, Key Laboratory of Molecular Imaging, Institute of Automation, Chinese Academy of Sciences, Beijing, 100190, China.
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12
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Jeffreys N, Brockman JM, Zhai Y, Ingber DE, Mooney DJ. Mechanical forces amplify TCR mechanotransduction in T cell activation and function. APPLIED PHYSICS REVIEWS 2024; 11:011304. [PMID: 38434676 PMCID: PMC10848667 DOI: 10.1063/5.0166848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 12/08/2023] [Indexed: 03/05/2024]
Abstract
Adoptive T cell immunotherapies, including engineered T cell receptor (eTCR) and chimeric antigen receptor (CAR) T cell immunotherapies, have shown efficacy in treating a subset of hematologic malignancies, exhibit promise in solid tumors, and have many other potential applications, such as in fibrosis, autoimmunity, and regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues to manipulate T cells ex vivo and in vivo, mechanical cues that regulate their biology have been largely underappreciated. This review highlights the contributions of mechanical force to several receptor-ligand interactions critical to T cell function, with central focus on the TCR-peptide-loaded major histocompatibility complex (pMHC). We then emphasize the role of mechanical forces in (i) allosteric strengthening of the TCR-pMHC interaction in amplifying ligand discrimination during T cell antigen recognition prior to activation and (ii) T cell interactions with the extracellular matrix. We then describe approaches to design eTCRs, CARs, and biomaterials to exploit TCR mechanosensitivity in order to potentiate T cell manufacturing and function in adoptive T cell immunotherapy.
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Affiliation(s)
| | | | - Yunhao Zhai
- Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, USA
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13
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Xiao Y, Xu RH, Dai Y. Nanoghosts: Harnessing Mesenchymal Stem Cell Membrane for Construction of Drug Delivery Platforms Via Optimized Biomimetics. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2304824. [PMID: 37653618 DOI: 10.1002/smll.202304824] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/10/2023] [Indexed: 09/02/2023]
Abstract
Mesenchymal stem cells (MSCs) are becoming hotspots for application in disease therapies recently, combining with biomaterials and drug delivery system. A major advantage of MSCs applied in drug delivery system is that these cells enable specific targeting and releasing of cargos to the disease sites. However, the potential tumor tropic effects of MSCs raised concerns on biosafety. To solve this problem, there are emerging methods of isolating cell membranes and developing nanoformulations to perform drug delivery, which avoids concerns on biosafety without disturbing the membrane functions of specific polarizing and locating. These cargoes are so called "nanoghosts." This review article summarizes the current applications of nanoghosts, the promising potential of MSCs to be applied in membrane isolation and nanoghost construction, and possible approaches to develop better drug delivery system harnessing from MSC ghost cell membranes.
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Affiliation(s)
- Yuan Xiao
- Faculty of Health Sciences and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, 999078, China
| | - Ren-He Xu
- Faculty of Health Sciences and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, 999078, China
| | - Yunlu Dai
- Faculty of Health Sciences and MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, 999078, China
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14
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Burmeister M, Frauenstein A, Kahms M, Arends L, Gerwien H, Deshpande T, Kuhlmann T, Gross CC, Naik VN, Wiendl H, Klingauf J, Meissner F, Sorokin L. Secretomics reveals gelatinase substrates at the blood-brain barrier that are implicated in astroglial barrier function. SCIENCE ADVANCES 2023; 9:eadg0686. [PMID: 37467333 PMCID: PMC10355830 DOI: 10.1126/sciadv.adg0686] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 06/15/2023] [Indexed: 07/21/2023]
Abstract
The gelatinases, matrix metalloproteinase 2 (MMP-2) and MMP-9, are key for leukocyte penetration of the brain parenchymal border in neuroinflammation and the functional integrity of this barrier; however, it is unclear which MMP substrates are involved. Using a tailored, sensitive, label-free mass spectrometry-based secretome approach, not previously applied to nonimmune cells, we identified 119 MMP-9 and 21 MMP-2 potential substrates at the cell surface of primary astrocytes, including known substrates (β-dystroglycan) and a broad spectrum of previously unknown MMP-dependent events involved in cell-cell and cell-matrix interactions. Using neuroinflammation as a model of assessing compromised astroglial barrier function, a selection of the potential MMP substrates were confirmed in vivo and verified in human samples, including vascular cell adhesion molecule-1 and neuronal cell adhesion molecule. We provide a unique resource of potential MMP-2/MMP-9 substrates specific for the astroglia barrier. Our data support a role for the gelatinases in the formation and maintenance of this barrier but also in astrocyte-neuron interactions.
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Affiliation(s)
- Miriam Burmeister
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Münster, Germany
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
| | | | - Martin Kahms
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
- Institute of Medical Physics and Biophysics, University of Muenster, Münster, Germany
| | - Laura Arends
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Münster, Germany
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
| | - Hanna Gerwien
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Münster, Germany
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
| | - Tushar Deshpande
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Münster, Germany
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
| | - Tanja Kuhlmann
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
- Institute of Neuropathology, University Hospital Muenster, Münster, Germany
| | - Catharina C. Gross
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
- Neurology Department., University Clinic, University of Muenster, Münster, Germany
| | - Venu N. Naik
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
- Neurology Department., University Clinic, University of Muenster, Münster, Germany
| | - Heinz Wiendl
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
- Neurology Department., University Clinic, University of Muenster, Münster, Germany
- Brain and Mind Center,, Sydney, New South Wales, Australia
| | - Juergen Klingauf
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
- Institute of Medical Physics and Biophysics, University of Muenster, Münster, Germany
| | - Felix Meissner
- Max-Planck Institute for Biochemistry, Martinsried, Germany
- Institute of Innate Immunity, Department of Systems Immunology and Proteomics, Medical Faculty, University of Bonn, Bonn, Germany
| | - Lydia Sorokin
- Institute of Physiological Chemistry and Pathobiochemistry, University of Muenster, Münster, Germany
- Cells-in-Motion Interfaculty Centre (CIMIC), University of Muenster, Münster, Germany
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15
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Han Z, Liu Q, Li H, Zhang M, You L, Lin Y, Wang K, Gou Q, Wang Z, Zhou S, Cai Y, Yuan L, Chen H. The role of monocytes in thrombotic diseases: a review. Front Cardiovasc Med 2023; 10:1113827. [PMID: 37332592 PMCID: PMC10272466 DOI: 10.3389/fcvm.2023.1113827] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 05/18/2023] [Indexed: 06/20/2023] Open
Abstract
Cardiovascular and cerebrovascular diseases are the number one killer threatening people's life and health, among which cardiovascular thrombotic events are the most common. As the cause of particularly serious cardiovascular events, thrombosis can trigger fatal crises such as acute coronary syndrome (myocardial infarction and unstable angina), cerebral infarction and so on. Circulating monocytes are an important part of innate immunity. Their main physiological functions are phagocytosis, removal of injured and senescent cells and their debris, and development into macrophages and dendritic cells. At the same time, they also participate in the pathophysiological processes of pro-coagulation and anticoagulation. According to recent studies, monocytes have been found to play a significant role in thrombosis and thrombotic diseases of the immune system. In this manuscript, we review the relationship between monocyte subsets and cardiovascular thrombotic events and analyze the role of monocytes in arterial thrombosis and their involvement in intravenous thrombolysis. Finally, we summarize the mechanism and therapeutic regimen of monocyte and thrombosis in hypertension, antiphospholipid syndrome, atherosclerosis, rheumatic heart disease, lower extremity deep venous thrombosis, and diabetic nephropathy.
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Affiliation(s)
- Zhongyu Han
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiong Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongpeng Li
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Meiqi Zhang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Luling You
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumeng Lin
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ke Wang
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiaoyin Gou
- Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhanzhan Wang
- Lianyungang Clinical College of Nanjing Medical University, Lianyungang, China
| | - Shuwei Zhou
- Department of Radiology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - YiJin Cai
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lan Yuan
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haoran Chen
- Science and Education Department, Chengdu Xinhua Hospital, Chengdu, China
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16
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Cohen CD, Rousseau ST, Bermea KC, Bhalodia A, Lovell JP, Dina Zita M, Čiháková D, Adamo L. Myocardial Immune Cells: The Basis of Cardiac Immunology. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1198-1207. [PMID: 37068299 PMCID: PMC10111214 DOI: 10.4049/jimmunol.2200924] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 01/14/2023] [Indexed: 04/19/2023]
Abstract
The mammalian heart is characterized by the presence of striated myocytes, which allow continuous rhythmic contraction from early embryonic development until the last moments of life. However, the myocardium contains a significant contingent of leukocytes from every major class. This leukocyte pool includes both resident and nonresident immune cells. Over recent decades, it has become increasingly apparent that the heart is intimately sensitive to immune signaling and that myocardial leukocytes exhibit an array of critical functions, both in homeostasis and in the context of cardiac adaptation to injury. Here, we systematically review current knowledge of all major leukocyte classes in the heart, discussing their functions in health and disease. We also highlight the connection between the myocardium, immune cells, lymphoid organs, and both local and systemic immune responses.
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Affiliation(s)
- Charles D. Cohen
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Sylvie T. Rousseau
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Kevin C. Bermea
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Aashik Bhalodia
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Jana P. Lovell
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Marcelle Dina Zita
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Daniela Čiháková
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States of America
| | - Luigi Adamo
- Cardiac Immunology Laboratory, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
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Zhang Q, Sioud M. Tumor-Associated Macrophage Subsets: Shaping Polarization and Targeting. Int J Mol Sci 2023; 24:7493. [PMID: 37108657 PMCID: PMC10138703 DOI: 10.3390/ijms24087493] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/12/2023] [Accepted: 04/16/2023] [Indexed: 04/29/2023] Open
Abstract
The tumor microenvironment (TME) is a critical regulator of tumor growth, progression, and metastasis. Among the innate immune cells recruited to the tumor site, macrophages are the most abundant cell population and are present at all stages of tumor progression. They undergo M1/M2 polarization in response to signals derived from TME. M1 macrophages suppress tumor growth, while their M2 counterparts exert pro-tumoral effects by promoting tumor growth, angiogenesis, metastasis, and resistance to current therapies. Several subsets of the M2 phenotype have been observed, often denoted as M2a, M2b, M2c, and M2d. These are induced by different stimuli and differ in phenotypes as well as functions. In this review, we discuss the key features of each M2 subset, their implications in cancers, and highlight the strategies that are being developed to harness TAMs for cancer treatment.
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Affiliation(s)
- Qindong Zhang
- Division of Cancer Medicine, Department of Cancer Immunology, Oslo University Hospital, University of Oslo, Ullernchausseen 70, 0379 Oslo, Norway
- Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Blindern, P.O. Box 1068, 0316 Oslo, Norway
| | - Mouldy Sioud
- Division of Cancer Medicine, Department of Cancer Immunology, Oslo University Hospital, University of Oslo, Ullernchausseen 70, 0379 Oslo, Norway
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18
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Gallanis GT, Sharif GM, Schmidt MO, Friedland BN, Battina R, Rahhal R, Davis JE, Khan IS, Wellstein A, Riegel AT. Stromal Senescence following Treatment with the CDK4/6 Inhibitor Palbociclib Alters the Lung Metastatic Niche and Increases Metastasis of Drug-Resistant Mammary Cancer Cells. Cancers (Basel) 2023; 15:1908. [PMID: 36980794 PMCID: PMC10046966 DOI: 10.3390/cancers15061908] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/05/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND CDK4/6 inhibitors (CDKi) have improved disease control in hormone-receptor-positive, HER2-negative metastatic breast cancer, but most patients develop progressive disease. METHODS We asked whether host stromal senescence after CDK4/6 inhibition affects metastatic seeding and growth of CDKi-resistant mammary cancer cells by using the p16-INK-ATTAC mouse model of inducible senolysis. RESULTS Palbociclib pretreatment of naïve mice increased lung seeding of CDKi-resistant syngeneic mammary cancer cells, and this effect was reversed by depletion of host senescent cells. RNA sequencing analyses of lungs from non-tumor-bearing p16-INK-ATTAC mice identified that palbociclib downregulates immune-related gene sets and gene expression related to leukocyte migration. Concomitant senolysis reversed a portion of these effects, including pathway-level enrichment of TGF-β- and senescence-related signaling. CIBERSORTx analysis revealed that palbociclib alters intra-lung macrophage/monocyte populations. Notably, lung metastases from palbociclib-pretreated mice revealed senescent endothelial cells. Palbociclib-treated endothelial cells exhibit hallmark senescent features in vitro, upregulate genes involved with the senescence-associated secretory phenotype, leukocyte migration, and TGF-β-mediated paracrine senescence and induce tumor cell migration and monocyte trans-endothelial invasion in co-culture. CONCLUSIONS These studies shed light on how stromal senescence induced by palbociclib affects lung metastasis, and they describe palbociclib-induced gene expression changes in the normal lung and endothelial cell models that correlate with changes in the tumor microenvironment in the lung metastatic niche.
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Affiliation(s)
| | | | - Marcel O. Schmidt
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | | | | | | | | | | | | | - Anna T. Riegel
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
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19
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Sun R, Shang J, Yan X, Zhao J, Wang W, Wang W, Li W, Gao C, Wang F, Zhang H, Wang Y, Cao H, Zhang J. VCAM1 Drives Vascular Inflammation Leading to Continuous Cortical Neuronal Loss Following Chronic Cerebral Hypoperfusion. J Alzheimers Dis 2023; 91:1541-1555. [PMID: 36641679 DOI: 10.3233/jad-221059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND Chronic cerebral hypoperfusion (CCH) is associated with neuronal loss and blood-brain barrier (BBB) impairment in vascular dementia (VaD). However, the relationship and the molecular mechanisms between BBB dysfunction and neuronal loss remain elusive. OBJECTIVE We explored the reasons for neuron loss following CCH. METHODS Using permanent bilateral common carotid artery occlusion (2VO) rat model, we observed the pathological changes of cortical neurons and BBB in the sham group as well as rats 3d, 7d, 14d and 28d post 2VO. In order to further explore the factors influencing neuron loss following CCH with regard to cortical blood vessels, we extracted cortical brain microvessels at five time points for transcriptome sequencing. Finally, integrin receptor a4β1 (VLA-4) inhibitor was injected into the tail vein, and cortical neuron loss was detected again. RESULTS We found that cortical neuron loss following CCH is a continuous process, but damage to the BBB is acute and transient. Results of cortical microvessel transcriptome analysis showed that biological processes related to vascular inflammation mainly occurred in the chronic phase. Meanwhile, cell adhesion molecules, cytokine-cytokine receptor interaction were significantly changed at this phase. Among them, the adhesion molecule VCAM1 plays an important role. Using VLA-4 inhibitor to block VCAM1-VLA-4 interaction, cortical neuron damage was ameliorated at 14d post 2VO. CONCLUSION Injury of the BBB may not be the main reason for persistent loss of cortical neurons following CCH. The continuous inflammatory response within blood vessels maybe an important factor in the continuous loss of cortical neurons following CCH.
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Affiliation(s)
- Ruihua Sun
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.,Department of Neurology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Junkui Shang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Xi Yan
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Jingran Zhao
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.,Department of Neurology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Wan Wang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.,Department of Neurology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Wenjing Wang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Wei Li
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Chenhao Gao
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Fengyu Wang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Haohan Zhang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China
| | - Yanliang Wang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.,Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Zhengzhou, Henan, China
| | - Huixia Cao
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.,Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan Provincial Clinical Research Center for Kidney Disease, Zhengzhou, Henan, China
| | - Jiewen Zhang
- Department of Neurology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.,Department of Neurology, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
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20
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M1/M2 re-polarization of kaempferol biomimetic NPs in anti-inflammatory therapy of atherosclerosis. J Control Release 2023; 353:1068-1083. [PMID: 36549391 DOI: 10.1016/j.jconrel.2022.12.041] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 12/02/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Atherosclerosis (AS), a leading cause of death worldwide, involves chronic macrophage inflammation from its initiation to the emergence of complications. Targeting plaque inflammation by re-polarizing pro-inflammatory M1 to anti-inflammatory M2 could therefore provide a promising strategy to treat AS, but currently available anti-inflammatory drugs limit clinical outcomes. In this study, we found that kaempferol (KPF) is capable of potential anti-inflammation as a novel drug candidate, which has been scarcely reported. Building upon these findings, we fabricated a macrophage-biomimetic KPF delivery platform, abbreviated as KPF@MM-NPs to potentiate therapeutic payloads, wherein the designed ROS-responsive Dextran-g-PBMEO NPs with π-π stacking were coated with macrophage membrane (MM) for effective target and accumulation in atherosclerotic lesions. Therapy of KPF@MM-NPs afforded significant decrease in proliferating macrophage inflammation while went with the reduction of key pro-inflammatory cytokines and re-polarization M1 to M2 phenotype, inducing excellent anti-AS responses in ApoE-/- mice after i.p. delivery. The mechanism of KPF@MM-NPs was further investigated and found it related to block the ROS/NF-κB signaling pathways. Together with as well demonstrated biosafety profiles, this proof-of-concept opens an instructive door for the study of KPF-mediated nanodrugs in treatment of AS based on biomimetic NPs.
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21
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VanHeyst KA, Choi SH, Kingsley DT, Huang AY. Ectopic Tumor VCAM-1 Expression in Cancer Metastasis and Therapy Resistance. Cells 2022; 11:cells11233922. [PMID: 36497180 PMCID: PMC9735769 DOI: 10.3390/cells11233922] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/23/2022] [Accepted: 12/01/2022] [Indexed: 12/12/2022] Open
Abstract
Vascular Cell Adhesion Molecule-1 (VCAM-1; CD106) is a membrane protein that contributes critical physiologic functional roles in cellular immune response, including leukocyte extravasation in inflamed and infected tissues. Expressed as a cell membrane protein, VCAM-1 can also be cleaved from the cell surface into a soluble form (sVCAM-1). The integrin α4β1 (VLA-4) was identified as the first major ligand for VCAM-1. Ongoing studies suggest that, in addition to mediating physiologic immune functions, VCAM-1/VLA-4 signaling plays an increasingly vital role in the metastatic progression of various tumors. Additionally, elevated concentrations of sVCAM-1 have been found in the peripheral blood of patients with cancer, suggesting the tumor microenvironment (TME) as the source of sVCAM-1. Furthermore, over-expression of VLA-4 was linked to tumor progression in various malignancies when VCAM-1 was also up-regulated. This review explores the functional role of VCAM-1 expression in cancer metastasis and therapy resistance, and the potential for the disruption of VCAM-1/VLA-4 signaling as a novel immunotherapeutic approach in cancer, including osteosarcoma, which disproportionately affects the pediatric, adolescent and young adult population, as an unmet medical need.
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Affiliation(s)
- Kristen A. VanHeyst
- Center for Pediatric Immunotherapy at Rainbow, Angie Fowler AYA Cancer Institute, Division of Pediatric Hematology-Oncology, UH Rainbow Babies and Children’s Hospital, Cleveland, OH 44106, USA
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Sung Hee Choi
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | | | - Alex Y. Huang
- Center for Pediatric Immunotherapy at Rainbow, Angie Fowler AYA Cancer Institute, Division of Pediatric Hematology-Oncology, UH Rainbow Babies and Children’s Hospital, Cleveland, OH 44106, USA
- Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Correspondence: ; Tel.: +1-216-368-1271
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22
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Yu M, Hong K, Adili R, Mei L, Liu L, He H, Guo Y, Chen YE, Holinstat M, Schwendeman A. Development of activated endothelial targeted high-density lipoprotein nanoparticles. Front Pharmacol 2022; 13:902269. [PMID: 36105190 PMCID: PMC9464908 DOI: 10.3389/fphar.2022.902269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/25/2022] [Indexed: 01/14/2023] Open
Abstract
Endothelial inflammation is an important pathophysiological driving force in various acute and chronic inflammatory diseases. High-density lipoproteins (HDLs) play critical roles in regulating endothelial functions and resolving endothelial inflammation. In the present study, we developed synthetic HDLs (sHDLs) which actively target inflamed endothelium through conjugating vascular cell adhesion protein 1 (VCAM-1) specific VHPK peptide. The active targeting of VHPK-sHDLs was confirmed in vitro on TNF-α activated endothelial cells. VHPK-sHDLs presented potent anti-inflammatory efficacies in vitro through the reduction of proinflammatory cytokine production and inhibition of leukocyte adhesion to activated endothelium. VHPK-sHDLs showed increased binding on inflamed vessels and alleviated LPS-induced lung inflammation in vivo. The activated endothelium-targeted sHDLs may be further optimized to resolve endothelial inflammation in various inflammatory diseases.
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Affiliation(s)
- Minzhi Yu
- Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
| | - Kristen Hong
- Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
| | - Reheman Adili
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Ling Mei
- Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
| | - Lisha Liu
- Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hongliang He
- Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
- State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Yanhong Guo
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, United States
| | - Y. Eugene Chen
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, United States
| | - Michael Holinstat
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, United States
| | - Anna Schwendeman
- Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, United States
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23
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Shedding Light on the Drug-Target Prediction of the Anti-Inflammatory Peptide TnP with Bioinformatics Tools. Pharmaceuticals (Basel) 2022; 15:ph15080994. [PMID: 36015142 PMCID: PMC9412873 DOI: 10.3390/ph15080994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022] Open
Abstract
Peptide–protein interactions are involved in various fundamental cellular functions, and their identification is crucial for designing efficacious peptide therapeutics. Drug–target interactions can be inferred by in silico prediction using bioinformatics and computational tools. We patented the TnP family of synthetic cyclic peptides, which is in the preclinical stage of developmental studies for chronic inflammatory diseases such as multiple sclerosis. In an experimental autoimmune enceph-alomyelitis model, we found that TnP controls neuroinflammation and prevents demyelination due to its capacity to cross the blood–brain barrier and to act in the central nervous system blocking the migration of inflammatory cells responsible for neuronal degeneration. Therefore, the identification of potential targets for TnP is the objective of this research. In this study, we used bioinformatics and computational approaches, as well as bioactivity databases, to evaluate TnP–target prediction for proteins that were not experimentally tested, specifically predicting the 3D structure of TnP and its biochemical characteristics, TnP–target protein binding and docking properties, and dynamics of TnP competition for the protein/receptor complex interaction, construction of a network of con-nectivity and interactions between molecules as a result of TnP blockade, and analysis of similarities with bioactive molecules. Based on our results, integrins were identified as important key proteins and considered responsible to regulate TnP-governed pharmacological effects. This comprehensive in silico study will help to understand how TnP induces its anti-inflammatory effects and will also facilitate the identification of possible side effects, as it shows its link with multiple biologically important targets in humans.
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24
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Labib D, Wang Z, Prakash P, Zimmer M, Smith MD, Frazel PW, Barbar L, Sapar ML, Calabresi PA, Peng J, Liddelow SA, Fossati V. Proteomic Alterations and Novel Markers of Neurotoxic Reactive Astrocytes in Human Induced Pluripotent Stem Cell Models. Front Mol Neurosci 2022; 15:870085. [PMID: 35592112 PMCID: PMC9113221 DOI: 10.3389/fnmol.2022.870085] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 03/29/2022] [Indexed: 12/20/2022] Open
Abstract
Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1α, and C1q ("TIC") has been implicated in many neurodegenerative diseases as a source of neurotoxicity. Here, we used an established human induced pluripotent stem cell (hiPSC) model to investigate the surface marker profile and proteome of TIC-induced reactive astrocytes. We propose VCAM1, BST2, ICOSL, HLA-E, PD-L1, and PDPN as putative, novel markers of this reactive sub-state. We found that several of these markers colocalize with GFAP+ cells in post-mortem samples from people with Alzheimer's disease. Moreover, our whole-cells proteomic analysis of TIC-induced reactive astrocytes identified proteins and related pathways primarily linked to potential engagement with peripheral immune cells. Taken together, our findings will serve as new tools to purify reactive astrocyte subtypes and to further explore their involvement in immune responses associated with injury and disease.
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Affiliation(s)
- David Labib
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Zhen Wang
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Priya Prakash
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, United States
| | - Matthew Zimmer
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Matthew D. Smith
- Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
| | - Paul W. Frazel
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, United States
| | - Lilianne Barbar
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Maria L. Sapar
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
| | - Peter A. Calabresi
- Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, United States
| | - Junmin Peng
- Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
- Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - Shane A. Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, United States
- Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY, United States
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, United States
- Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, United States
| | - Valentina Fossati
- The New York Stem Cell Foundation Research Institute, New York, NY, United States
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25
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Shin MJ, Park JY, Lee DH, Khang D. Stem Cell Mimicking Nanoencapsulation for Targeting Arthritis. Int J Nanomedicine 2022; 16:8485-8507. [PMID: 35002240 PMCID: PMC8725870 DOI: 10.2147/ijn.s334298] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Accepted: 12/05/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are considered a promising regenerative therapy due to their ability to migrate toward damaged tissues. The homing ability of MSCs is unique compared with that of non-migrating cells and MSCs are considered promising therapeutic vectors for targeting major cells in many pathophysiological sites. MSCs have many advantages in the treatment of malignant diseases, particularly rheumatoid arthritis (RA). RA is a representative autoimmune disease that primarily affects joints, and secreted chemokines in the joints are well recognized by MSCs following their migration to the joints. Furthermore, MSCs can regulate the inflammatory process and repair damaged cells in the joints. However, the functionality and migration ability of MSCs injected in vivo still show insufficient. The targeting ability and migration efficiency of MSCs can be enhanced by genetic engineering or modification, eg, overexpressing chemokine receptors or migration-related genes, thus maximizing their therapeutic effect. However, there are concerns about genetic changes due to the increased probability of oncogenesis resulting from genome integration of the viral vector, and thus, clinical application is limited. Furthermore, it is suspected that administering MSCs can promote tumor growth and metastasis in xenograft and orthotopic models. For this reason, MSC mimicking nanoencapsulations are an alternative strategy that does not involve using MSCs or bioengineered MSCs. MSC mimicking nanoencapsulations consist of MSC membrane-coated nanoparticles, MSC-derived exosomes and artificial ectosomes, and MSC membrane-fused liposomes with natural or genetically engineered MSC membranes. MSC mimicking nanoencapsulations not only retain the targeting ability of MSCs but also have many advantages in terms of targeted drug delivery. Specifically, MSC mimicking nanoencapsulations are capable of encapsulating drugs with various components, including chemotherapeutic agents, nucleic acids, and proteins. Furthermore, there are fewer concerns over safety issues on MSC mimicking nanoencapsulations associated with mutagenesis even when using genetically engineered MSCs, because MSC mimicking nanoencapsulations use only the membrane fraction of MSCs. Genetic engineering is a promising route in clinical settings, where nano-encapsulated technology strategies are combined. In this review, the mechanism underlying MSC homing and the advantages of MSC mimicking nanoencapsulations are discussed. In addition, genetic engineering of MSCs and MSC mimicking nanoencapsulation is described as a promising strategy for the treatment of immune-related diseases.
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Affiliation(s)
- Min Jun Shin
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea
| | - Jun Young Park
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea
| | - Dae Ho Lee
- Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, 21999, South Korea.,Department of Internal Medicine, Gachon University College of Medicine, Incheon, 21999, South Korea
| | - Dongwoo Khang
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, South Korea.,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, South Korea.,Department of Physiology, School of Medicine, Gachon University, Incheon, 21999, South Korea
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26
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Design of α/β-Hybrid Peptide Ligands of α4β1 Integrin Equipped with a Linkable Side Chain for Chemoselective Biofunctionalization of Microstructured Materials. Biomedicines 2021; 9:biomedicines9111737. [PMID: 34829965 PMCID: PMC8615975 DOI: 10.3390/biomedicines9111737] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 12/22/2022] Open
Abstract
Arg-Gly-Asp (RGD)-binding integrins, e.g., αvβ3, αvβ1, αvβ5 integrins, are currently regarded as privileged targets for the delivery of diagnostic and theranostic agents, especially in cancer treatment. In contrast, scarce attention has been paid so far to the diagnostic opportunities promised by integrins that recognize other peptide motifs. In particular, α4β1 integrin is involved in inflammatory, allergic, and autoimmune diseases, therefore, it represents an interesting therapeutic target. Aiming at obtaining simple, highly stable ligands of α4β1 integrin, we designed hybrid α/β peptidomimetics carrying linkable side chains for the expedient functionalization of biomaterials, nano- and microparticles. We identified the prototypic ligands MPUPA-(R)-isoAsp(NHPr)-Gly-OH (12) and MPUPA-Dap(Ac)-Gly-OH (13) (MPUPA, methylphenylureaphenylacetic acid; Dap, 2,3-diamino propionic acid). Modification of 12 and 13 by introduction of flexible linkers at isoAsp or Dap gave 49 and 50, respectively, which allowed for coating with monolayers (ML) of flat zeolite crystals. The resulting peptide–zeolite MLs were able to capture selectively α4β1 integrin-expressing cells. In perspective, the α4β1 integrin ligands identified in this study can find applications for preparing biofunctionalized surfaces and diagnostic devices to control the progression of α4β1 integrin-correlated diseases.
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27
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Rapraeger AC. Syndecans and Their Synstatins: Targeting an Organizer of Receptor Tyrosine Kinase Signaling at the Cell-Matrix Interface. Front Oncol 2021; 11:775349. [PMID: 34778093 PMCID: PMC8578902 DOI: 10.3389/fonc.2021.775349] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/27/2021] [Indexed: 01/11/2023] Open
Abstract
Receptor tyrosine kinases (RTKs) and integrin matrix receptors have well-established roles in tumor cell proliferation, invasion and survival, often functioning in a coordinated fashion at sites of cell-matrix adhesion. Central to this coordination are syndecans, another class of matrix receptor, that organize RTKs and integrins into functional units, relying on docking motifs in the syndecan extracellular domains to capture and localize RTKs (e.g., EGFR, IGF-1R, VEGFR2, HER2) and integrins (e.g., αvβ3, αvβ5, α4β1, α3β1, α6β4) to sites of adhesion. Peptide mimetics of the docking motifs in the syndecans, called “synstatins”, prevent assembly of these receptor complexes, block their signaling activities and are highly effective against tumor cell invasion and survival and angiogenesis. This review describes our current understanding of these four syndecan-coupled mechanisms and their inhibitory synstatins (SSTNIGF1R, SSTNVEGFR2, SSTNVLA-4, SSTNEGFR and SSTNHER2).
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Affiliation(s)
- Alan C Rapraeger
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
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28
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Khan IM, Ulrich BJ, Nelson AS, Sehra S, Kansas GS, Kaplan MH. Selectin Dependence of Allergic Skin Inflammation Is Diminished by Maternal Atopy. Immunohorizons 2021; 5:703-710. [PMID: 34433625 PMCID: PMC8638165 DOI: 10.4049/immunohorizons.2100052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/04/2021] [Indexed: 11/19/2022] Open
Abstract
Allergic skin inflammation requires the influx of inflammatory cells into the skin. Extravasation of leukocytes into the skin requires interactions between endothelial selectins and their glycan ligands on the surface of leukocytes. Selectin-ligand formation requires the activity of several glycosyltransferases, including Fut7 In this report, we tested the importance of Fut7 for the development of allergic skin inflammation in the Stat6VT transgenic mouse model. We observed that Fut7 deficiency was protective but did not eliminate disease. Segregation of the data by gender of the parent that transmitted the Stat6VT transgene, but not by gender of the pups, which were analyzed for disease, revealed that the protective effects of Fut7 deficiency were significantly greater when dams were Stat6VT negative. In contrast, in mice from litters of Stat6VT+ dams, Fut7 deficiency resulted in only modest protection. These findings indicate that pups from atopic dams exhibit a greater propensity for allergic disease, similar to observations in humans, and that the effect of maternal atopy is due to enhanced selectin-independent mechanisms of leukocyte recruitment in their offspring. Together, these results demonstrate that Fut7 deficiency can be protective in a model of atopic dermatitis but that maternal atopy diminishes these protective effects, suggesting alternative pathways for leukocyte recruitment in the absence of Fut7 enzyme activity. These observations have implications for understanding how the environment in utero predisposes for the development of allergic disease.
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Affiliation(s)
- Ibrahim M Khan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
| | - Benjamin J Ulrich
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
| | - Andrew S Nelson
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; and
| | - Sarita Sehra
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; and
| | - Geoffrey S Kansas
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Mark H Kaplan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN;
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; and
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Sottoriva K, Pajcini KV. Notch Signaling in the Bone Marrow Lymphopoietic Niche. Front Immunol 2021; 12:723055. [PMID: 34394130 PMCID: PMC8355626 DOI: 10.3389/fimmu.2021.723055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Lifelong mammalian hematopoiesis requires continuous generation of mature blood cells that originate from Hematopoietic Stem and Progenitor Cells (HSPCs) situated in the post-natal Bone Marrow (BM). The BM microenvironment is inherently complex and extensive studies have been devoted to identifying the niche that maintains HSPC homeostasis and supports hematopoietic potential. The Notch signaling pathway is required for the emergence of the definitive Hematopoietic Stem Cell (HSC) during embryonic development, but its role in BM HSC homeostasis is convoluted. Recent work has begun to explore novel roles for the Notch signaling pathway in downstream progenitor populations. In this review, we will focus an important role for Notch signaling in the establishment of a T cell primed sub-population of Common Lymphoid Progenitors (CLPs). Given that its activation mechanism relies primarily on cell-to-cell contact, Notch signaling is an ideal means to investigate and define a novel BM lymphopoietic niche. We will discuss how new genetic model systems indicate a pre-thymic, BM-specific role for Notch activation in early T cell development and what this means to the paradigm of lymphoid lineage commitment. Lastly, we will examine how leukemic T-cell acute lymphoblastic leukemia (T-ALL) blasts take advantage of Notch and downstream lymphoid signals in the pathological BM niche.
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Affiliation(s)
- Kilian Sottoriva
- Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL, United States
| | - Kostandin V Pajcini
- Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago College of Medicine, Chicago, IL, United States
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30
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Gholizadeh M, Saeedy SAG, Roodi PB, Saedisomeolia A. The association between zinc and endothelial adhesion molecules ICAMs and VCAM-1 and nuclear receptors PPAR-ɑ and PPAR-γ: A systematic review on cell culture, animal and human studies. Microvasc Res 2021; 138:104217. [PMID: 34197877 DOI: 10.1016/j.mvr.2021.104217] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/12/2021] [Accepted: 06/24/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Cardiovascular health is strongly influenced by diet. The levels of inflammatory factors like ICAM-1 and VCAM-1 are high in patients with atherosclerosis or predisposing factor for heart disease. Antioxidant and anti-inflammatory functions are attributed to zinc. We systematically reviewed cell culture, human or animal studies for determining the relationship between zinc status and ICAMs or VCAM-1 levels. METHODS PubMed, Google Scholar, Scopus, and Cochrane databases from database inception till 30th August 2020 were systematically searched to obtain any possible article for inclusion. RESULTS After screening and removing unrelated or duplicate articles by the title and abstract by two independent reviewers, 15 articles were included. Results indicating an inverse relationship between zinc status with ICAM-1 or VCAM-1 levels and the development of endothelial inflammation, plaque formation, or atherosclerosis. A direct relationship between zinc status and PPAR-α or γ levels was also observed. Zinc oxide (ZnO), zinc nanoparticles, or ions can cause endothelial activation and increased levels of ICAM-1 and VCAM-1. CONCLUSION Normal function of the endothelium is linked with zinc level. Zinc deficiency causes atherosclerosis, most probably via increased production of ICAM-1 and VCAM-1; and decreased expression of PPAR-ɑ and PPAR-γ receptors. Contrarily, endothelial activation and increased ICAM-1 and VCAM-1 levels can be caused by ZnO, zinc nanoparticles, or zinc ions.
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Affiliation(s)
- Mohammad Gholizadeh
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Poorya Basafay Roodi
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ahmad Saedisomeolia
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.
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Induced Pluripotent Stem Cell-Derived Conditioned Medium Promotes Endogenous Leukemia Inhibitory Factor to Attenuate Endotoxin-Induced Acute Lung Injury. Int J Mol Sci 2021; 22:ijms22115554. [PMID: 34074039 PMCID: PMC8197417 DOI: 10.3390/ijms22115554] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
The conditioned medium of induced pluripotent stem cells (iPSC-CM) can attenuate neutrophil recruitment and endothelial leakage of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Therefore, we investigated the mechanisms by which iPSC-CM regulate the interaction between neutrophils and the endothelium in ALI. Murine iPSCs (miPSCs) were delivered intravenously to male C57BL/6 mice (8–12 weeks old) 4 h after intratracheal LPS injection. A miPSC-derived conditioned medium (miPSC-CM) was delivered intravenously to mice after intratracheal LPS injection. DMSO-induced HL-60 cells (D-HL-60, neutrophil-like cells) and human umbilical vein endothelial cells (HUVECs) were used as in vitro models to assess the interaction of neutrophils and endothelial cells. miPSC-CM diminished the histopathological changes in the lungs and the neutrophil count in bronchoalveolar lavage fluids of ALI mice. miPSC-CM attenuated the expression of adhesion molecules in the lungs of ALI mice. Human iPSC conditioned medium (hiPSC-CM) reduced the expression of adhesion molecules in a HUVEC and D-HL-60 co-culture after LPS stimulation, which decreased the transendothelial migration (TEM) of D-HL-60. A human angiogenesis factors protein array revealed that leukemia inhibitory factor (LIF) was not detected in the absence of D-HL-60 and hiPSC-CM groups. hiPSC-CM significantly promoted the production of endogenous LIF in in vitro models. Administration of an anti-LIF antibody not only reversed the effect of iPSC-CM in ALI mice, but also blocked the effect of iPSC-CM on neutrophils TEM in in vitro models. However, a controlled IgG had no such effect. Our study demonstrated that iPSC-CM promoted endogenous LIF to inhibit neutrophils TEM and attenuate the severity of sepsis-induced ALI.
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32
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Integrin VLA-4 as a PET imaging biomarker of hyper-adhesion in transgenic sickle mice. Blood Adv 2021; 4:4102-4112. [PMID: 32882004 DOI: 10.1182/bloodadvances.2020002642] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
In sickle cell disease (SCD), very late antigen-4 (VLA-4 or integrin α4β1) mediates the adhesion of reticulocytes to inflamed, proinflammatory endothelium, a key process in promoting vaso-occlusive episodes (VOEs). We hypothesized that a radionuclide tracer targeting VLA-4 could be harnessed as a positron emission tomography (PET) imaging biomarker of VOEs. We tested the VLA-4 peptidomimetic PET tracer 64Cu-CB-TE1A1P-PEG4-LLP2A (64Cu-LLP2A) for imaging hyper-adhesion-associated VOEs in the SCD Townes mouse model. With lipopolysaccharide (LPS)-induced VOEs, 64Cu-LLP2A uptake was increased in the bone marrow of the humeri and femurs, common sites of VOEs in SCD mice compared with non-SCD mice. Treatment with a proven inhibitor of VOEs (the anti-mouse anti-P-selectin monoclonal antibody [mAb] RB40.34) during LPS stimulation led to a reduction in the uptake of 64Cu-LLP2A in the humeri and femurs to baseline levels, implying blockade of VOE hyper-adhesion. Flow cytometry with Cy3-LLP2A demonstrated an increased percentage of VLA-4-positive reticulocytes in SCD vs non-SCD mice in the bone and peripheral blood after treatment with LPS, which was abrogated by anti-P-selectin mAb treatment. These data, for the first time, show in vivo imaging of VLA-4-mediated hyper-adhesion, primarily of SCD reticulocytes, during VOEs. PET imaging with 64Cu-LLP2A may serve as a valuable, noninvasive method for identifying sites of vaso-occlusion and may provide an objective biomarker of disease severity and anti-P-selectin treatment efficacy in patients with SCD.
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Wei Q, Singh O, Ekinci C, Gill J, Li M, Mamatjan Y, Karimi S, Bunda S, Mansouri S, Aldape K, Zadeh G. TNFα secreted by glioma associated macrophages promotes endothelial activation and resistance against anti-angiogenic therapy. Acta Neuropathol Commun 2021; 9:67. [PMID: 33853689 PMCID: PMC8048292 DOI: 10.1186/s40478-021-01163-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023] Open
Abstract
One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs.
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34
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Robert P, Biarnes-Pelicot M, Garcia-Seyda N, Hatoum P, Touchard D, Brustlein S, Nicolas P, Malissen B, Valignat MP, Theodoly O. Functional Mapping of Adhesiveness on Live Cells Reveals How Guidance Phenotypes Can Emerge From Complex Spatiotemporal Integrin Regulation. Front Bioeng Biotechnol 2021; 9:625366. [PMID: 33898401 PMCID: PMC8058417 DOI: 10.3389/fbioe.2021.625366] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/05/2021] [Indexed: 01/13/2023] Open
Abstract
Immune cells have the ubiquitous capability to migrate disregarding the adhesion properties of the environment, which requires a versatile adaptation of their adhesiveness mediated by integrins, a family of specialized adhesion proteins. Each subtype of integrins has several ligands and several affinity states controlled by internal and external stimuli. However, probing cell adhesion properties on live cells without perturbing cell motility is highly challenging, especially in vivo. Here, we developed a novel in vitro method using micron-size beads pulled by flow to functionally probe the local surface adhesiveness of live and motile cells. This method allowed a functional mapping of the adhesiveness mediated by VLA-4 and LFA-1 integrins on the trailing and leading edges of live human T lymphocytes. We show that cell polarization processes enhance integrin-mediated adhesiveness toward cell rear for VLA-4 and cell front for LFA-1. Furthermore, an inhibiting crosstalk of LFA-1 toward VLA-4 and an activating crosstalk of VLA-4 toward LFA-1 were found to modulate cell adhesiveness with a long-distance effect across the cell. These combined signaling processes directly support the bistable model that explains the emergence of the versatile guidance of lymphocyte under flow. Molecularly, Sharpin, an LFA-1 inhibitor in lymphocyte uropod, was found involved in the LFA-1 deadhesion of lymphocytes; however, both Sharpin and Myosin inhibition had a rather modest impact on adhesiveness. Quantitative 3D immunostaining identified high-affinity LFA-1 and VLA-4 densities at around 50 and 100 molecules/μm2 in basal adherent zones, respectively. Interestingly, a latent adhesiveness of dorsal zones was not grasped by immunostaining but assessed by direct functional assays with beads. The combination of live functional assays, molecular imaging, and genome editing is instrumental to characterizing the spatiotemporal regulation of integrin-mediated adhesiveness at molecular and cell scales, which opens a new perspective to decipher sophisticated phenotypes of motility and guidance.
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Affiliation(s)
- Philippe Robert
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Martine Biarnes-Pelicot
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Nicolas Garcia-Seyda
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Petra Hatoum
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Dominique Touchard
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Sophie Brustlein
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Philippe Nicolas
- Aix-Marseille University, CNRS, INSERM U1104 Centre d'immunologie de Marseille-Luminy, Marseille, France
| | - Bernard Malissen
- Aix-Marseille University, CNRS, INSERM U1104 Centre d'immunologie de Marseille-Luminy, Marseille, France
| | - Marie-Pierre Valignat
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
| | - Olivier Theodoly
- LAI, Aix-Marseille University, CNRS, INSERM U1067 Adhésion Cellulaires et lnflammation, Turing Center for Living Systems, Marseille, France
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35
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Mehatre SH, Roy IM, Biswas A, Prit D, Schouteden S, Huelsken J, Verfaillie CM, Khurana S. Niche-Mediated Integrin Signaling Supports Steady-State Hematopoiesis in the Spleen. THE JOURNAL OF IMMUNOLOGY 2021; 206:1549-1560. [PMID: 33637617 DOI: 10.4049/jimmunol.2001066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 01/20/2021] [Indexed: 11/19/2022]
Abstract
Outside-in integrin signaling regulates cell fate decisions in a variety of cell types, including hematopoietic stem cells (HSCs). Our earlier published studies showed that interruption of periostin (POSTN) and integrin-αv (ITGAV) interaction induces faster proliferation in HSCs with developmental stage-dependent functional effects. In this study, we examined the role of POSTN-ITGAV axis in lymphohematopoietic activity in spleen that hosts a rare population of HSCs, the functional regulation of which is not clearly known. Vav-iCre-mediated deletion of Itgav in the hematopoietic system led to higher proliferation rates, resulting in increased frequency of primitive HSCs in the adult spleen. However, in vitro CFU-C assays demonstrated a poorer differentiation potential following Itgav deletion. This also led to a decrease in the white pulp area with a significant decline in the B cell numbers. Systemic deletion of its ligand, POSTN, phenocopied the effects noted in Vav-Itgav-/- mice. Histological examination of Postn-deficient spleen also showed an increase in the spleen trabecular areas. Importantly, these are the myofibroblasts of the trabecular and capsular areas that expressed high levels of POSTN within the spleen tissue. In addition, vascular smooth muscle cells also expressed POSTN. Through CFU-S12 assays, we showed that hematopoietic support potential of stroma in Postn-deficient splenic hematopoietic niche was defective. Overall, we demonstrate that POSTN-ITGAV interaction plays an important role in spleen lymphohematopoiesis.
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Affiliation(s)
- Shubham Haribhau Mehatre
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Irene Mariam Roy
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Atreyi Biswas
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Devila Prit
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India
| | - Sarah Schouteden
- Interdepartmental Stem Cell Institute, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; and
| | - Joerg Huelsken
- École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
| | - Catherine M Verfaillie
- Interdepartmental Stem Cell Institute, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; and
| | - Satish Khurana
- School of Biology, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India;
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36
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Luzentales-Simpson M, Pang YCF, Zhang A, Sousa JA, Sly LM. Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases. Front Cell Dev Biol 2021; 9:612830. [PMID: 33614645 PMCID: PMC7887288 DOI: 10.3389/fcell.2021.612830] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/12/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.
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Affiliation(s)
- Matthew Luzentales-Simpson
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Yvonne C F Pang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Ada Zhang
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - James A Sousa
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
| | - Laura M Sly
- Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC, Canada
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VCAM-1 Target in Non-Invasive Imaging for the Detection of Atherosclerotic Plaques. BIOLOGY 2020; 9:biology9110368. [PMID: 33138124 PMCID: PMC7692297 DOI: 10.3390/biology9110368] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023]
Abstract
Simple Summary Cardiovascular diseases are the first cause of morbimortality worldwide. They are mainly caused by atherosclerosis, with progressive plaque formation in the arterial wall. In this context, several imaging techniques have been developed to screen, detect and quantify atherosclerosis. Early screening improves primary prevention and promotes the prescription of adequate medication before adverse clinical events. In this review, we focus on the imaging of vascular cell adhesion molecule-1, an adhesion molecule involved in the first stages of the development of atherosclerosis. This molecule could therefore be a promising target to detect early atherosclerosis non-invasively. Potential clinical applications are critically discussed. Abstract Atherosclerosis is a progressive chronic arterial disease characterised by atheromatous plaque formation in the intima of the arterial wall. Several invasive and non-invasive imaging techniques have been developed to detect and characterise atherosclerosis in the vessel wall: anatomic/structural imaging, functional imaging and molecular imaging. In molecular imaging, vascular cell adhesion molecule-1 (VCAM-1) is a promising target for the non-invasive detection of atherosclerosis and for the assessment of novel antiatherogenic treatments. VCAM-1 is an adhesion molecule expressed on the activated endothelial surface that binds leucocyte ligands and therefore promotes leucocyte adhesion and transendothelial migration. Hence, for several years, there has been an increase in molecular imaging methods for detecting VCAM-1 in MRI, PET, SPECT, optical imaging and ultrasound. The use of microparticles of iron oxide (MPIO), ultrasmall superparamagnetic iron oxide (USPIO), microbubbles, echogenic immunoliposomes, peptides, nanobodies and other nanoparticles has been described. However, these approaches have been tested in animal models, and the remaining challenge is bench-to-bedside development and clinical applicability.
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Park EJ, Myint PK, Ito A, Appiah MG, Darkwah S, Kawamoto E, Shimaoka M. Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin. Front Cell Dev Biol 2020; 8:588066. [PMID: 33195249 PMCID: PMC7649757 DOI: 10.3389/fcell.2020.588066] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 10/05/2020] [Indexed: 01/10/2023] Open
Abstract
Integrins are transmembrane proteins that mediate cellular adhesion and migration to neighboring cells or the extracellular matrix, which is essential for cells to undertake diverse physiological and pathological pathways. For integrin activation and ligand binding, bidirectional signaling across the cell membrane is needed. Integrins aberrantly activated under pathologic conditions facilitate cellular infiltration into tissues, thereby causing inflammatory or tumorigenic progressions. Thus, integrins have emerged to the forefront as promising targets for developing therapeutics to treat autoimmune and cancer diseases. In contrast, it remains a fact that integrin-ligand interactions are beneficial for improving the health status of different tissues. Among these ligands, irisin, a myokine produced mainly by skeletal muscles in an exercise-dependent manner, has been shown to bind to integrin αVβ5, alleviating symptoms under unfavorable conditions. These findings may provide insights into some of the underlying mechanisms by which exercise improves quality of life. This review will discuss the current understanding of integrin-ligand interactions in both health and disease. Likewise, we not only explain how diverse ligands play different roles in mediating cellular functions under both conditions via their interactions with integrins, but also specifically highlight the potential roles of the emerging ligand irisin in inflammation, cancer, and metabolic disease.
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Affiliation(s)
- Eun Jeong Park
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Phyoe Kyawe Myint
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Atsushi Ito
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.,Department of Thoracic and Cardiovascular Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Michael G Appiah
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Samuel Darkwah
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Eiji Kawamoto
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan.,Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan
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Zhang D, Bi J, Liang Q, Wang S, Zhang L, Han F, Li S, Qiu B, Fan X, Chen W, Jiao H, Ye Y, Ding Y. VCAM1 Promotes Tumor Cell Invasion and Metastasis by Inducing EMT and Transendothelial Migration in Colorectal Cancer. Front Oncol 2020; 10:1066. [PMID: 32793471 PMCID: PMC7390920 DOI: 10.3389/fonc.2020.01066] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 05/28/2020] [Indexed: 12/20/2022] Open
Abstract
Vascular cell adhesion molecular 1 (VCAM1), an important member of the immunoglobulin superfamily, is related to the development of malignant tumors, such as breast cancer, melanoma, and renal clear cell carcinoma. However, the molecular role and mechanism of VCAM1 in the regulation of the progression of colorectal cancer (CRC) has rarely been studied. The results of IHC and RT-PCR analyses proved that VCAM1 was upregulated in human CRC tissues compared with matched adjacent normal intestinal epithelial tissues. Moreover, analysis of data from the TCGA and Gene Expression Omnibus (GEO) databases revealed that a higher level of VCAM1 was strongly correlated with poor differentiation, metastasis, and short survival in CRC patients. Furthermore, VCAM1 significantly influenced the invasion and metastasis of CRC cells in vitro and in vivo and activated the EMT program, by which cancer cells adhere to the endothelium and cross the vessel wall by forming pseudopodia and invadopodia. The current findings demonstrate that VCAM1 promotes tumor progression in CRC.
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Affiliation(s)
- Dan Zhang
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Jiaxin Bi
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Qiaoyan Liang
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Shuyang Wang
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Lingjie Zhang
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Fangyi Han
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Shengnan Li
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Bowen Qiu
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Xingdi Fan
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Wei Chen
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Hongli Jiao
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Yaping Ye
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
| | - Yanqing Ding
- Department of Pathology, School of Basic Medical Sciences and Nanfang Hospital, Southern Medical University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, China
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40
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Zheng G, Xie ZY, Wang P, Wu YF, Shen HY. Recent advances of single-cell RNA sequencing technology in mesenchymal stem cell research. World J Stem Cells 2020; 12:438-447. [PMID: 32742561 PMCID: PMC7360991 DOI: 10.4252/wjsc.v12.i6.438] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/13/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with great potential for clinical applications. However, little is known about their cell heterogeneity at a single-cell resolution, which severely impedes the development of MSC therapy. In this review, we focus on advances in the identification of novel surface markers and functional subpopulations of MSCs made by single-cell RNA sequencing and discuss their participation in the pathophysiology of stem cells and related diseases. The challenges and future directions of single-cell RNA sequencing in MSCs are also addressed in this review.
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Affiliation(s)
- Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Zhong-Yu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Yan-Feng Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Hui-Yong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
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41
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Pievani A, Biondi M, Tomasoni C, Biondi A, Serafini M. Location First: Targeting Acute Myeloid Leukemia Within Its Niche. J Clin Med 2020; 9:E1513. [PMID: 32443460 PMCID: PMC7290711 DOI: 10.3390/jcm9051513] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 12/15/2022] Open
Abstract
Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.
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Affiliation(s)
- Alice Pievani
- Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, 20900 Monza, Italy; (A.P.); (M.B.); (C.T.)
| | - Marta Biondi
- Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, 20900 Monza, Italy; (A.P.); (M.B.); (C.T.)
| | - Chiara Tomasoni
- Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, 20900 Monza, Italy; (A.P.); (M.B.); (C.T.)
| | - Andrea Biondi
- Department of Pediatrics, Pediatric Hematology-Oncology Unit, Fondazione MBBM/San Gerardo Hospital, 20900 Monza, Italy;
| | - Marta Serafini
- Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, 20900 Monza, Italy; (A.P.); (M.B.); (C.T.)
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VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects. Int J Mol Sci 2020; 21:ijms21062206. [PMID: 32210016 PMCID: PMC7139737 DOI: 10.3390/ijms21062206] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/18/2020] [Accepted: 03/20/2020] [Indexed: 12/16/2022] Open
Abstract
Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.
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43
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MacKay L, Khadra A. The bioenergetics of integrin-based adhesion, from single molecule dynamics to stability of macromolecular complexes. Comput Struct Biotechnol J 2020; 18:393-416. [PMID: 32128069 PMCID: PMC7044673 DOI: 10.1016/j.csbj.2020.02.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 12/22/2022] Open
Abstract
The forces actively generated by motile cells must be transmitted to their environment in a spatiotemporally regulated manner, in order to produce directional cellular motion. This task is accomplished through integrin-based adhesions, large macromolecular complexes that link the actin-cytoskelton inside the cell to its external environment. Despite their relatively large size, adhesions exhibit rapid dynamics, switching between assembly and disassembly in response to chemical and mechanical cues exerted by cytoplasmic biochemical signals, and intracellular/extracellular forces, respectively. While in material science, force typically disrupts adhesive contact, in this biological system, force has a more nuanced effect, capable of causing assembly or disassembly. This initially puzzled experimentalists and theorists alike, but investigation into the mechanisms regulating adhesion dynamics have progressively elucidated the origin of these phenomena. This review provides an overview of recent studies focused on the theoretical understanding of adhesion assembly and disassembly as well as the experimental studies that motivated them. We first concentrate on the kinetics of integrin receptors, which exhibit a complex response to force, and then investigate how this response manifests itself in macromolecular adhesion complexes. We then turn our attention to studies of adhesion plaque dynamics that link integrins to the actin-cytoskeleton, and explain how force can influence the assembly/disassembly of these macromolecular structure. Subsequently, we analyze the effect of force on integrins populations across lengthscales larger than single adhesions. Finally, we cover some theoretical studies that have considered both integrins and the adhesion plaque and discuss some potential future avenues of research.
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Affiliation(s)
- Laurent MacKay
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada
| | - Anmar Khadra
- Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada
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44
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Peptide-based nanosystems for vascular cell adhesion molecule-1 targeting: a real opportunity for therapeutic and diagnostic agents in inflammation associated disorders. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2019.101461] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Perivascular Lymphocyte Clusters Induced by Gastric Subserous Layer Vaccination Mediate Optimal Immunity against Helicobacter through Facilitating Immune Cell Infiltration and Local Antibody Response. J Immunol Res 2020; 2020:1480281. [PMID: 32411786 PMCID: PMC7201474 DOI: 10.1155/2020/1480281] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 12/19/2019] [Indexed: 01/16/2023] Open
Abstract
Background In situ vaccination-induced local inflammatory response resulted in the establishment of a pool of tissue-resident memory T (TRM) cells and new vessels after the resolution of inflammation. TRM cells have received increasing attention; however, the role of new vessels in protective response is still unknown. Materials and Methods We performed the laparotomy to access the stomach and injected alum-based vaccine into the gastric subserous layer (GSL). At 28 days post vaccination, a parabiosis mouse model along with depletion of anti-CD90.2 antibody was employed to explore the function of perivascular lymphocyte clusters in recall responses. The composition of the gastric lymphocyte clusters was analyzed by immunofluorescence staining. Antibody responses were detected using ELISA. Gastric lymphocytes were analyzed using flow cytometry. Results GSL vaccination induced the formation of new vessels in the inflamed region. These new vessels were different from native vessels in that they were generally accompanied by perivascular lymphocyte clusters that mainly consisted of CD90-expressing cells. Additionally, histological analysis revealed the presence of CD4+ and CD8+ T cells in the perivascular lymphocyte clusters. Administration of a dose of an anti-CD90.2 antibody to GSL-vaccinated mice resolved these clusters. The efficacy of protection was compared in the parabiosis mice. Upon challenge, the presence of perivascular lymphocyte clusters was responsible for the fast recall response, as depletion of these clusters by CD90.2 antibody administration resulted in decreased expressions of VCAM-1, Madcam-1, and TNF-α, as well as lower recruitment of proinflammatory immune cells, decreased antibody levels, and poor protection. Conclusions Our research demonstrates that in situ vaccination-induced regional inflammatory response contributes to optimal recall response not only by establishing a CD4+ TRM pool but also by creating an “expressway,” i.e., perivascular lymphocyte cluster.
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Hornung A, Sbarrato T, Garcia-Seyda N, Aoun L, Luo X, Biarnes-Pelicot M, Theodoly O, Valignat MP. A Bistable Mechanism Mediated by Integrins Controls Mechanotaxis of Leukocytes. Biophys J 2019; 118:565-577. [PMID: 31928762 DOI: 10.1016/j.bpj.2019.12.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 11/28/2019] [Accepted: 12/11/2019] [Indexed: 10/25/2022] Open
Abstract
Recruitment of leukocytes from blood vessels to inflamed zones is guided by biochemical and mechanical stimuli, with the mechanisms only partially deciphered. Here, we studied the guidance by the flow of primary human effector T lymphocytes crawling on substrates coated with ligands of integrins lymphocyte function-associated antigen 1 (LFA-1) (αLβ2) and very late antigen 4 (VLA-4) (α4β1). We reveal that cells segregate in two populations of opposite orientation for combined adhesion and show that decisions of orientation rely on a bistable mechanism between LFA-1-mediated upstream and VLA-4-mediated downstream phenotypes. At the molecular level, bistability results from a differential front-rear polarization of both integrin affinities, combined with an inhibiting cross talk of LFA-1 toward VLA-4. At the cellular level, direction is determined by the passive, flow-mediated orientation of the nonadherent cell parts, the rear uropod for upstream migration, and the front lamellipod for downstream migration. This chain of logical events provides a comprehensive mechanism of guiding, from stimuli to cell orientation.
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Affiliation(s)
| | - Thomas Sbarrato
- Aix Marseille University, CNRS, INSERM, LAI, Marseille, France
| | | | - Laurene Aoun
- Aix Marseille University, CNRS, INSERM, LAI, Marseille, France
| | - Xuan Luo
- Aix Marseille University, CNRS, INSERM, LAI, Marseille, France
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Jung O, Beauvais DM, Adams KM, Rapraeger AC. VLA-4 phosphorylation during tumor and immune cell migration relies on its coupling to VEGFR2 and CXCR4 by syndecan-1. J Cell Sci 2019; 132:jcs.232645. [PMID: 31562188 DOI: 10.1242/jcs.232645] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 09/20/2019] [Indexed: 12/19/2022] Open
Abstract
When targeted by the tumor-promoting enzyme heparanase, cleaved and shed syndecan-1 (Sdc1) then couples VEGFR2 (also known as KDR) to VLA-4, activating VEGFR2 and the directed migration of myeloma cells. But how VEGFR2 activates VLA-4-mediated motility has remained unknown. We now report that VEGFR2 causes PKA-mediated phosphorylation of VLA-4 on S988, an event known to stimulate tumor metastasis while suppressing cytotoxic immune cells. A key partner in this mechanism is the chemokine receptor CXCR4, a well-known mediator of cell motility in response to gradients of the chemokine SDF-1 (also known as CXCL12). The entire machinery necessary to phosphorylate VLA-4, consisting of CXCR4, AC7 (also known as ADCY7) and PKA, is constitutively associated with VEGFR2 and is localized to the integrin by Sdc1. VEGFR2 carries out the novel phosphorylation of Y135 within the DRY microswitch of CXCR4, sequentially activating Gαiβγ, AC7 and PKA, which phosphorylates S988 on the integrin. This mechanism is blocked by a syndecan-mimetic peptide (SSTNVEGFR2), which, by preventing VEGFR2 linkage to VLA-4, arrests tumor cell migration that depends on VLA-4 phosphorylation and stimulates the LFA-1-mediated migration of cytotoxic leukocytes.
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Affiliation(s)
- Oisun Jung
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA.,Graduate Program in Molecular and Cellular Pharmacology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - DeannaLee M Beauvais
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Kristin M Adams
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
| | - Alan C Rapraeger
- Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA .,Graduate Program in Molecular and Cellular Pharmacology, School of Medicine and Public Health, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, USA
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A Spatially Resolved and Quantitative Model of Early Atherosclerosis. Bull Math Biol 2019; 81:4022-4068. [PMID: 31392575 DOI: 10.1007/s11538-019-00646-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 07/10/2019] [Indexed: 01/01/2023]
Abstract
Atherosclerosis is a major burden for all societies, and there is a great need for a deeper understanding of involved key inflammatory, immunological and biomechanical processes. A decisive step for the prevention and medical treatment of atherosclerosis is to predict what conditions determine whether early atherosclerotic plaques continue to grow, stagnate or become regressive. The driving biological and mechanobiological mechanisms that determine the stability of plaques are yet not fully understood. We develop a spatially resolved and quantitative mathematical model of key contributors of early atherosclerosis. The stability of atherosclerotic model plaques is assessed to identify and classify progression-prone and progression-resistant atherosclerotic regions based on measurable or computable in vivo inputs, such as blood cholesterol concentrations and wall shear stresses. The model combines Darcy's law for the transmural flow through vessels walls, the Kedem-Katchalsky equations for endothelial fluxes of lipoproteins, a quantitative model of early plaque formation from a recent publication and a novel submodel for macrophage recruitment. The parameterization and analysis of the model suggest that the advective flux of lipoproteins through the endothelium is decisive, while the influence of the advective transport within the artery wall is negligible. Further, regions in arteries with an approximate wall shear stress exposure below 20% of the average exposure and their surroundings are potential regions where progression-prone atherosclerotic plaques develop.
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Schulz M, Salamero-Boix A, Niesel K, Alekseeva T, Sevenich L. Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis. Front Immunol 2019; 10:1713. [PMID: 31396225 PMCID: PMC6667643 DOI: 10.3389/fimmu.2019.01713] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 07/09/2019] [Indexed: 12/14/2022] Open
Abstract
Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ. It has long been regarded as an immunological sanctuary site where the presence of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCB) restricts the entry of immune cells from the periphery. Consequently, tumor cells that metastasize to the brain were thought to be shielded from systemic immune surveillance and destruction. However, the detailed characterization of the immune landscape within border-associated areas of the central nervous system (CNS), such as the meninges and the choroid plexus, as well as the discovery of lymphatics and channels that connect the CNS with the periphery, have recently challenged the dogma of the immune privileged status of the brain. Moreover, the presence of brain metastases (BrM) disrupts the integrity of the BBB and BCB. Indeed, BrM induce the recruitment of different immune cells from the myeloid and lymphoid lineage to the CNS. Blood-borne immune cells together with brain-resident cell-types, such as astrocytes, microglia, and neurons, form a highly complex and dynamic TME that affects tumor cell survival and modulates the mode of immune responses that are elicited by brain metastatic tumor cells. In this review, we will summarize recent findings on heterotypic interactions within the brain metastatic TME and highlight specific functions of brain-resident and recruited cells at different rate-limiting steps of the metastatic cascade. Based on the insight from recent studies, we will discuss new opportunities and challenges for TME-targeted and immunotherapies for BrM.
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Affiliation(s)
- Michael Schulz
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.,Biological Sciences, Faculty 15, Goethe University, Frankfurt, Germany
| | - Anna Salamero-Boix
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Katja Niesel
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Tijna Alekseeva
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany
| | - Lisa Sevenich
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany.,German Cancer Consortium (DKTK, Partner Site Frankfurt/Mainz) and German Cancer Research Center (DKFZ), Heidelberg, Germany
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50
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Regulation of cell migration by α4 and α9 integrins. Biochem J 2019; 476:705-718. [PMID: 30819933 DOI: 10.1042/bcj20180415] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 02/09/2019] [Accepted: 02/12/2019] [Indexed: 12/15/2022]
Abstract
Integrins are heterodimeric transmembrane receptors that play an essential role in enabling cells to sense and bind to extracellular ligands. Activation and clustering of integrins leads to the formation of focal adhesions at the plasma membrane that subsequently initiate signalling pathways to control a broad range of functional endpoints including cell migration, proliferation and survival. The α4 and α9 integrins form a small sub-family of receptors that share some specific ligands and binding partners. Although relatively poorly studied compared with other integrin family members, emerging evidence suggests that despite restricted cell and tissue expression profiles, these integrins play a key role in the regulation of signalling pathways controlling cytoskeletal remodelling and migration in both adherent and non-adherent cell types. This review summarises the known shared and specific roles for α4 and α9 integrins and highlights the importance of these receptors in controlling cell migration within both homeostatic and disease settings.
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