|
1
|
Wang Y, Anesi JC, Panicker IS, Cook D, Bista P, Fang Y, Oqueli E. Neuroimmune Interactions and Their Role in Immune Cell Trafficking in Cardiovascular Diseases and Cancer. Int J Mol Sci 2025; 26:2553. [PMID: 40141195 PMCID: PMC11941982 DOI: 10.3390/ijms26062553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 02/26/2025] [Accepted: 03/11/2025] [Indexed: 03/28/2025] Open
Abstract
Sympathetic nerves innervate bone marrow and various immune organs, where norepinephrine-the primary sympathetic neurotransmitter-directly interacts with immune cells that express adrenergic receptors. This article reviewed the key molecular pathways triggered by sympathetic activation and explored how sympathetic activity influences immune cell migration. Norepinephrine serves as a chemoattractant for monocytes, macrophages, and stem cells, promoting the migration of myeloid cells while inhibiting the migration of lymphocytes at physiological concentrations. We also examined the role of immune cell infiltration in cardiovascular diseases and cancer. Evidence suggests that sympathetic activation increases myeloid cell infiltration into target tissues across various cardiovascular diseases, including atherosclerosis, hypertension, cardiac fibrosis, cardiac hypertrophy, arrhythmia, myocardial infarction, heart failure, and stroke. Conversely, inhibiting sympathetic activity may serve as a potential therapeutic strategy to treat these conditions by reducing macrophage infiltration. Furthermore, sympathetic activation promotes macrophage accumulation in cancer tissues, mirroring its effects in cardiovascular diseases, while suppressing T lymphocyte infiltration into cancerous sites. These changes contribute to increased cancer growth and metastasis. Thus, inhibiting sympathetic activation could help to protect against cancer by enhancing T cell infiltration and reducing macrophage presence in tumors.
Collapse
Affiliation(s)
- Yutang Wang
- Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3353, Australia
| | - Jack C. Anesi
- Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3353, Australia
| | - Indu S. Panicker
- Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3353, Australia
| | - Darcy Cook
- Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3353, Australia
| | - Prapti Bista
- Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3353, Australia
| | - Yan Fang
- Discipline of Life Science, Institute of Innovation, Science and Sustainability, Federation University Australia, Ballarat, VIC 3353, Australia
| | - Ernesto Oqueli
- Cardiology Department, Grampians Health Ballarat, Ballarat, VIC 3353, Australia
- School of Medicine, Faculty of Health, Deakin University, Geelong, VIC 3217, Australia
| |
Collapse
|
|
2
|
Upadhyay S, Murugu L, Svensson L. Tumor cells escape immunosurveillance by hampering LFA-1. Front Immunol 2025; 16:1519841. [PMID: 39911389 PMCID: PMC11794523 DOI: 10.3389/fimmu.2025.1519841] [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: 10/30/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
During tumor immunosurveillance, leukocytes play a crucial role in the cellular defense system, working collaboratively with other immune components to recognize and eliminate aberrant cells. Integral to this process is the integrin Lymphocyte Function-Associated Antigen 1 (LFA-1). LFA-1 facilitates adhesion during leukocyte migration and helps establish stable cell-to-cell contacts between leukocytes and their targets. Additionally, as a receptor, LFA-1 signaling activates leukocytes, promoting their differentiation and effector functions against cancer. However, tumors can develop mechanisms to evade immune clearance by disrupting LFA-1 functions or hijacking its pathways. In this review, we first detail how leukocytes utilize LFA-1 during immunosurveillance and then explore how tumors counteract this process in the tumor microenvironment (TME) by either altering LFA-1 functions or exploiting it to drive tumorigenesis. Moreover, we discuss therapeutic strategies targeting LFA-1, including inhibitors tested in laboratory studies and animal models, highlighting their potential as anticancer interventions and the need for further research to evaluate their clinical utility.
Collapse
Affiliation(s)
| | - Lewis Murugu
- Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Lena Svensson
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
| |
Collapse
|
|
3
|
Wu Y, Cao Z, Liu W, Cahoon JG, Wang K, Wang P, Hu L, Chen Y, Moser M, Vella AT, Ley K, Wen L, Fan Z. Nanoscopy reveals integrin clustering reliant on kindlin-3 but not talin-1. Cell Commun Signal 2025; 23:12. [PMID: 39773732 PMCID: PMC11707915 DOI: 10.1186/s12964-024-02024-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 12/30/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Neutrophils are the most abundant leukocytes in human blood, and their recruitment is essential for innate immunity and inflammatory responses. The initial and critical step of neutrophil recruitment is their adhesion to vascular endothelium, which depends on G protein-coupled receptor (GPCR) triggered integrin inside-out signaling that induces β2 integrin activation and clustering on neutrophils. Kindlin-3 and talin-1 are essential regulators for the inside-out signaling induced β2 integrin activation. However, their contribution in the inside-out signaling induced β2 integrin clustering is unclear because conventional assays on integrin clustering are usually performed on adhered cells, where integrin-ligand binding concomitantly induces integrin outside-in signaling. METHODS We used flow cytometry and quantitative super-resolution stochastic optical reconstruction microscopy (STORM) to quantify β2 integrin activation and clustering, respectively, in kindlin-3 and talin-1 knockout leukocytes. We also tested whether wildtype or Pleckstrin homology (PH) domain deleted kindlin-3 can rescue the kindlin-3 knockout phenotypes. RESULTS GPCR-triggered inside-out signaling alone can induce β2 integrin clustering. As expected, both kindlin-3 and talin-1 knockout decreases integrin activation. Interestingly, only kindlin-3 but not talin-1 contributes to integrin clustering in the scenario of inside-out-signaling, wherein a critical role of the PH domain of kindlin-3 was highlighted. CONCLUSIONS Since talin was known to facilitate integrin clustering in outside-in-signaling-involved cells, our finding provides a paradigm shift by suggesting that the molecular mechanisms of integrin clustering upon inside-out signaling and outside-in signaling are different. Our data also contradict the conventional assumption that integrin activation and clustering are tightly inter-connected by showing separated regulation of the two during inside-out signaling. Our study provides a new mechanism that shows kindlin-3 regulates β2 integrin clustering and suggests that integrin clustering should be assessed independently, aside from integrin activation, when studying leukocyte adhesion in inflammatory diseases.
Collapse
Affiliation(s)
- Yuanyuan Wu
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Ziming Cao
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Wei Liu
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Jason G Cahoon
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Kepeng Wang
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Penghua Wang
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Liang Hu
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yunfeng Chen
- Department of Biochemistry and Molecular Biology, Department of Pathology, University of Texas Medical Branch, Galveston, Texas, 77555, USA
| | - Markus Moser
- Institute of Experimental Hematology, School of Medicine, Technical University of Munich, 81675, Munich, Germany
| | - Anthony T Vella
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA
| | - Klaus Ley
- Immunology Center of Georgia, Augusta University, Augusta, Georgia, 30912, USA
| | - Lai Wen
- Department of Pharmacology, University of Nevada School of Medicine, Reno, Nevada, 89557, USA.
| | - Zhichao Fan
- Department of Immunology, University of Connecticut School of Medicine, Connecticut, Farmington, 06030, USA.
| |
Collapse
|
|
4
|
Bongrand P. Should Artificial Intelligence Play a Durable Role in Biomedical Research and Practice? Int J Mol Sci 2024; 25:13371. [PMID: 39769135 PMCID: PMC11676049 DOI: 10.3390/ijms252413371] [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: 10/09/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
During the last decade, artificial intelligence (AI) was applied to nearly all domains of human activity, including scientific research. It is thus warranted to ask whether AI thinking should be durably involved in biomedical research. This problem was addressed by examining three complementary questions (i) What are the major barriers currently met by biomedical investigators? It is suggested that during the last 2 decades there was a shift towards a growing need to elucidate complex systems, and that this was not sufficiently fulfilled by previously successful methods such as theoretical modeling or computer simulation (ii) What is the potential of AI to meet the aforementioned need? it is suggested that recent AI methods are well-suited to perform classification and prediction tasks on multivariate systems, and possibly help in data interpretation, provided their efficiency is properly validated. (iii) Recent representative results obtained with machine learning suggest that AI efficiency may be comparable to that displayed by human operators. It is concluded that AI should durably play an important role in biomedical practice. Also, as already suggested in other scientific domains such as physics, combining AI with conventional methods might generate further progress and new applications, involving heuristic and data interpretation.
Collapse
Affiliation(s)
- Pierre Bongrand
- Laboratory Adhesion and Inflammation (LAI), Inserm UMR 1067, Cnrs Umr 7333, Aix-Marseille Université UM 61, 13009 Marseille, France
| |
Collapse
|
|
5
|
Hostler AC, Hahn WW, Hu MS, Rennert R, Fischer KS, Barrera JA, Duscher D, Januszyk M, Henn D, Sivaraj D, Yasmeh JP, Kussie HC, Granoski MB, Padmanabhan J, Vial IN, Riegler J, Wu JC, Longaker MT, Chen K, Maan ZN, Gurtner GC. Endothelial-specific CXCL12 regulates neovascularization during tissue repair and tumor progression. FASEB J 2024; 38:e70210. [PMID: 39698751 DOI: 10.1096/fj.202401307r] [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: 07/02/2024] [Revised: 11/08/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024]
Abstract
C-X-C motif chemokine ligand 12 (CXCL12; Stromal Cell-Derived Factor 1 [SDF-1]), most notably known for its role in embryogenesis and hematopoiesis, has been implicated in tumor pathophysiology and neovascularization. However, its cell-specific role and mechanism of action have not been well characterized. Previous work by our group has demonstrated that hypoxia-inducible factor (HIF)-1 modulates downstream CXCL12 expression following ischemic tissue injury. By utilizing a conditional CXCL12 knockout murine model, we demonstrate that endothelial-specific deletion of CXCL12 (eKO) modulates ischemic tissue survival, altering tissue repair and tumor progression without affecting embryogenesis and morphogenesis. Loss of endothelial-specific CXCL12 disrupts critical endothelial-fibroblast crosstalk necessary for stromal growth and vascularization. Using murine parabiosis with novel transcriptomic technologies, we demonstrate that endothelial-specific CXCL12 signaling results in downstream recruitment of non-inflammatory circulating cells, defined by neovascularization modulating genes. These findings indicate an essential role for endothelial-specific CXCL12 expression during the neovascular response in tissue injury and tumor progression.
Collapse
Affiliation(s)
- Andrew C Hostler
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
| | - William W Hahn
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Michael S Hu
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Robert Rennert
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Katharina S Fischer
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Janos A Barrera
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Dominik Duscher
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Michael Januszyk
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Dominic Henn
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Dharshan Sivaraj
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Jonathan P Yasmeh
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Hudson C Kussie
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Maia B Granoski
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Jagannath Padmanabhan
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Ivan N Vial
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Johannes Riegler
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA
| | - Michael T Longaker
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Kellen Chen
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Zeshaan N Maan
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| | - Geoffrey C Gurtner
- Department of Surgery, The University of Arizona College of Medicine, Tucson, Arizona, USA
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Palo Alto, California, USA
| |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
Muller WA. A physiologic roll for cell surface GlycoRNAs. J Leukoc Biol 2024; 115:996-998. [PMID: 38527802 PMCID: PMC11661460 DOI: 10.1093/jleuko/qiae073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 03/13/2024] [Accepted: 03/16/2024] [Indexed: 03/27/2024] Open
Abstract
Glycosylated RNA molecules that can be bound by lectins have been demonstrated on the surfaces of leukocytes, but their physiologic function(s) was not known. A recent study (PMID 38262409) demonstrates that at least 1 function is to promote capture and rolling of neutrophils in the vasculature. Of interest, the neutrophil glycosylated RNA molecules bind to P-selectin but not E-selectin.
Collapse
Affiliation(s)
- William A Muller
- Department of Pathology, Northwestern University Feinberg School of Medicine, Ward Building, Room 3-126, 303 East Chicago Avenue, Chicago, IL 60611, United States
| |
Collapse
|
|
8
|
Zhang J, Yao Z. Immune cell trafficking: a novel perspective on the gut-skin axis. Inflamm Regen 2024; 44:21. [PMID: 38654394 DOI: 10.1186/s41232-024-00334-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
Immune cell trafficking, an essential mechanism for maintaining immunological homeostasis and mounting effective responses to infections, operates under a stringent regulatory framework. Recent advances have shed light on the perturbation of cell migration patterns, highlighting how such disturbances can propagate inflammatory diseases from their origin to distal organs. This review collates and discusses current evidence that demonstrates atypical communication between the gut and skin, which are conventionally viewed as distinct immunological spheres, in the milieu of inflammation. We focus on the aberrant, reciprocal translocation of immune cells along the gut-skin axis as a pivotal factor linking intestinal and dermatological inflammatory conditions. Recognizing that the translation of these findings into clinical practices is nascent, we suggest that therapeutic strategies aimed at modulating the axis may offer substantial benefits in mitigating the widespread impact of inflammatory diseases.
Collapse
Affiliation(s)
- Jiayan Zhang
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhirong Yao
- Dermatology Center, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
9
|
Montoya M, Gallus M, Phyu S, Haegelin J, de Groot J, Okada H. A Roadmap of CAR-T-Cell Therapy in Glioblastoma: Challenges and Future Perspectives. Cells 2024; 13:726. [PMID: 38727262 PMCID: PMC11083543 DOI: 10.3390/cells13090726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/20/2024] [Accepted: 04/20/2024] [Indexed: 05/13/2024] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median overall survival of less than 2 years and a nearly 100% mortality rate under standard therapy that consists of surgery followed by combined radiochemotherapy. Therefore, new therapeutic strategies are urgently needed. The success of chimeric antigen receptor (CAR) T cells in hematological cancers has prompted preclinical and clinical investigations into CAR-T-cell treatment for GBM. However, recent trials have not demonstrated any major success. Here, we delineate existing challenges impeding the effectiveness of CAR-T-cell therapy for GBM, encompassing the cold (immunosuppressive) microenvironment, tumor heterogeneity, T-cell exhaustion, local and systemic immunosuppression, and the immune privilege inherent to the central nervous system (CNS) parenchyma. Additionally, we deliberate on the progress made in developing next-generation CAR-T cells and novel innovative approaches, such as low-intensity pulsed focused ultrasound, aimed at surmounting current roadblocks in GBM CAR-T-cell therapy.
Collapse
Affiliation(s)
- Megan Montoya
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Marco Gallus
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Su Phyu
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Jeffrey Haegelin
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - John de Groot
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
| | - Hideho Okada
- Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA
- Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
| |
Collapse
|
|
10
|
Vo Q, Carlson KA, Chiknas PM, Brocker CN, DaSilva L, Clark E, Park SK, Ajiboye AS, Wier EM, Benam KH. On-Chip Reconstitution of Uniformly Shear-Sensing 3D Matrix-embedded Multicellular Blood Microvessel. ADVANCED FUNCTIONAL MATERIALS 2024; 34:2304630. [PMID: 38465199 PMCID: PMC10923530 DOI: 10.1002/adfm.202304630] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Indexed: 03/12/2024]
Abstract
Preclinical human-relevant modeling of organ-specific vasculature offers a unique opportunity to recreate pathophysiological intercellular, tissue-tissue, and cell-matrix interactions for a broad range of applications. Here, we present a reliable, and simply reproducible process for constructing user-controlled long rounded extracellular matrix (ECM)-embedded vascular microlumens on-chip for endothelization and co-culture with stromal cells obtained from human lung. We demonstrate the critical impact of microchannel cross-sectional geometry and length on uniform distribution and magnitude of vascular wall shear stress, which is key when emulating in vivo-observed blood flow biomechanics in health and disease. In addition, we provide an optimization protocol for multicellular culture and functional validation of the system. Moreover, we show the ability to finely tune rheology of the three-dimensional natural matrix surrounding the vascular microchannel to match pathophysiological stiffness. In summary, we provide the scientific community with a matrix-embedded microvasculature on-chip populated with all-primary human-derived pulmonary endothelial cells and fibroblasts to recapitulate and interrogate lung parenchymal biology, physiological responses, vascular biomechanics, and disease biogenesis in vitro. Such a mix-and-match synthetic platform can be feasibly adapted to study blood vessels, matrix, and ECM-embedded cells in other organs and be cellularized with additional stromal cells.
Collapse
Affiliation(s)
- Quoc Vo
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Kaely A. Carlson
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Peter M. Chiknas
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Chad N. Brocker
- Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Luis DaSilva
- Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Erica Clark
- Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Sang Ki Park
- Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - A. Seun Ajiboye
- Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Eric M. Wier
- Center for Tobacco Products, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Kambez H. Benam
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
- Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15219, USA
- Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
| |
Collapse
|
|
11
|
Nash GB. The rheology of interactions between leukocytes, platelets and the vessel wall in thrombo-inflammation. Biorheology 2024; 59:63-80. [PMID: 38461497 DOI: 10.3233/bir-230040] [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] [Indexed: 03/12/2024]
Abstract
Leukocytes and platelets must adhere to the wall of blood vessels to carry out their protective functions in inflammation and haemostasis. Recruitment is critically dependent on rheological variables (wall shear rate and stress, red cell aggregation and haematocrit) which affect delivery to the vessel wall as well as velocities and forces experienced there. Leukocyte recruitment is efficient only up to wall shear rates of about 300 s-1 and usually restricted to low-shear post-capillary venules in inflammation. Being smaller, platelets experience lower velocities and shear forces adjacent to the wall and can adhere at much higher shear rates for haemostasis in arteries. In addition, we found quite different effects of variations in haematocrit or red cell aggregation on attachment of neutrophils or platelets, which also assist their separate recruitment in venules or arteries. However, it has become increasingly evident that inflammatory and thrombotic responses may occur together, with platelets promoting the adhesion and activation of neutrophils and monocytes. Indeed, it is 30 years since we demonstrated that platelets could cause neutrophils to aggregate in suspension and, when attached to a surface, could support selectin-mediated rolling of all leukocytes. Thrombin-activated platelets could further induce neutrophil activation and immobilisation. In some conditions, platelets could bind to intact endothelial monolayers and capture neutrophils or monocytes. Subsequently, we found that extracellular vesicles released by activated platelets (PEV) fulfilled similar functions when deposited on surfaces or bound to endothelial cells. In murine models, platelets or PEV could act as bridges for monocytes in inflamed vessels. Thus, leukocytes and platelets are rheologically adapted for their separate functions, while novel thrombo-inflammatory pathways using platelets or PEV may underlie pathogenic leukocyte recruitment.
Collapse
Affiliation(s)
- Gerard B Nash
- Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| |
Collapse
|
|
12
|
Brown F, Hill M, Renshaw D, Pedlar C, Hill J, van Someren K, Howatson G, Tallis J. The effect of medical grade compression garments on the repeated-bout effect in non-resistance-trained men. Exp Physiol 2023; 108:1490-1499. [PMID: 37768013 PMCID: PMC10988506 DOI: 10.1113/ep091399] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023]
Abstract
NEW FINDINGS What is the central question of this study? What are the effects of compression garments on recovery from unaccustomed damaging exercise and subsequent protective adaptations? What is the main finding and its importance? Compression did not influence recovery, but was associated with blunted protective adaptations for isokinetic performance, which were completely absent at high velocities. Based on these findings, the use of compression garments for recovery would not be recommended following unaccustomed exercise, particularly if the maintenance of high-velocity performance following exercise-induced muscle damage is desirable. ABSTRACT Whilst compression garments (CG) may enhance recovery from exercise-induced muscle damage (EIMD), many recovery strategies can attenuate adaptative responses. Therefore, the effects of CG on recovery from EIMD, and the rapid protective adaptations known as the repeated bout effect (RBE) were investigated. Thirty-four non-resistance-trained males (18-45 years) randomly received class II medical-grade CG or placebo for 72 h following eccentrically-focused lower-body exercise, in a double-blind, randomised controlled trial. Indices of EIMD were assessed at baseline, 0, 24, 48 and 72 h post-exercise, before exercise and testing were repeated after 14 days. Results were analysed using a three-way (time × condition × bout) linear mixed-effects model. Exercise impaired isometric and isokinetic strength, with soreness and thigh circumference elevated for 72 h (P < 0.001). Compression did not enhance recovery (P > 0.05), despite small to moderate effect sizes (ES, reported alongside 90% confidence intervals) for isokinetic strength (ES from 0.2 [-0.41, 0.82] to 0.65 [0.03, 1.28]). All variables recovered faster after the repeated bout (P < 0.005). However, RBE for peak isokinetic force was impaired in CG at 60° s-1 (group × bout interaction: χ2 = 4.24, P = 0.0395; ES = -0.56 [-1.18, 0.07]) and completely absent at 120° s-1 (χ2 = 16.2, P < 0.001, ES = -0.96 [-1.61, -0.32]) and 180° s-1 (χ2 = 10.4, P = 0.001, ES = -0.72 [-1.35, -0.09]). Compression blunted RBE at higher isokinetic velocities without improving recovery in non-resistance-trained males, potentially contraindicating their use following unaccustomed exercise in this population.
Collapse
Affiliation(s)
- Freddy Brown
- School of Life SciencesCoventry UniversityCoventryUK
- Research Centre for Physical Activity, Sport and Exercise ScienceCoventry UniversityCoventryUK
| | - Matt Hill
- Research Centre for Physical Activity, Sport and Exercise ScienceCoventry UniversityCoventryUK
| | - Derek Renshaw
- Centre for Health and Life SciencesCoventry UniversityCoventryUK
| | - Charles Pedlar
- Faculty of Sport, Health and Applied ScienceSt Mary's UniversityTwickenhamUK
- Institute of Sport, Exercise and Health, Division of Surgery and Interventional ScienceUniversity College LondonLondonUK
| | - Jessica Hill
- Faculty of Sport, Health and Applied ScienceSt Mary's UniversityTwickenhamUK
| | - Ken van Someren
- Sports Lab NorthwestAtlantic Technological UniversityDonegalIreland
| | - Glyn Howatson
- Faculty of Health and Life of SciencesNorthumbria UniversityNewcastle Upon TyneUK
- Water Research GroupNorthwest UniversityPotchefstroomSouth Africa
| | - Jason Tallis
- Research Centre for Physical Activity, Sport and Exercise ScienceCoventry UniversityCoventryUK
| |
Collapse
|
|
13
|
Du Y, Zhou L, Wen Z, Feng L, Zhang S, Zhang T. Slit2 suppresses endotoxin-induced uveitis by inhibiting the PI3K/Akt/IKK/NF-κB pathway. Scand J Immunol 2023; 98:e13319. [PMID: 38441217 DOI: 10.1111/sji.13319] [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: 03/08/2023] [Revised: 06/17/2023] [Accepted: 07/18/2023] [Indexed: 03/07/2024]
Abstract
Uveitis is a devastating intraocular inflammatory disease. The secreted leucine-rich repeat protein slit homologue 2 (Slit2) has been found to be an essential regulator of inflammation. This study aimed to analyse the anti-inflammatory effects and the underlying mechanisms of Slit2 in an endotoxin-induced uveitis (EIU) rat model. In this study, rats with EIU pretreated recombinant human Slit2 (rhSlit2) or a control vehicle by intravitreal injection. The clinical scores were graded under a slit lamp. The protein concentrations and total number of cells in the aqueous humour (AqH) were examined, and the retinal expression of various inflammatory mediators was detected. The levels of nuclear factor-kappa B (NF-κB), phosphorylated NF-κB, IkappaB-a (IκB-a), phosphorylated IκB-a, IKK, phosphorylated IKK, PI3Kp85, phosphorylated PI3Kp85, Akt and phosphorylated Akt were evaluated by western blotting. Treatment with rhSlit2 dramatically diminished the clinical scores of EIU, with significant decreases in inflammatory cell infiltration, protein concentrations, cellulose-like exudates, the production of ICAM-1, MCP-1, TNF-α and IL-6 in the AqH; and adhesion of leucocytes. The PI3K/Akt/IKK/NF-κB pathway was found to be activated in EIU. However, the pre-treatment of rhSlit2 significantly inhibited the production of ICAM-1, MCP-1, TNF-α, and IL-6, and inhibited leucocyte adhesion by modulating the PI3K/Akt/IKK/NF-κB pathway. In conclusion, the intravitreal injection of rhSlit2 alleviated EIU-related inflammation in Sprague-Dawley rats by reducing the proinflammatory cytokines and leucocyte adhesion; in particular, rhSlit2 may inhibit LPS-induced inflammation by inhibiting the activation of PI3K/Akt/IKK/NF-κB signalling pathway. Therefore, rhSlit2 shows significant potential for effectively alleviating immune inflammatory responses in vivo.
Collapse
Affiliation(s)
- Yong Du
- Chongqing Key Lab of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China
| | - Linbin Zhou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Zijun Wen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| | - Lujia Feng
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, China
| | - Shaochong Zhang
- Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, Shenzhen, China
| | - Ting Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China
| |
Collapse
|
|
14
|
Belyaev AV, Fedotova IV. Molecular mechanisms of catch bonds and their implications for platelet hemostasis. Biophys Rev 2023; 15:1233-1256. [PMID: 37974999 PMCID: PMC10643804 DOI: 10.1007/s12551-023-01144-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/07/2023] [Indexed: 11/19/2023] Open
Abstract
Adhesive molecular bonds between blood cells are essential for thrombosis and hemostasis as they provide means for platelet adhesion, aggregation, and signaling in flowing blood. According to the nowadays conventional definition, a "catch" bond is a type of non-covalent bio-molecular bridge, whose dissociation lifetime counter-intuitively increases with applied tensile force. Following recent experimental findings, such receptor-ligand protein bonds are vital to the blood cells involved in the prevention of bleeding (hemostatic response) and infection (immunity). In this review, we examine the up-to-date experimental discoveries and theoretical insights about catch bonds between the blood cells, their biomechanical principles at the molecular level, and their role in platelet thrombosis and hemostasis.
Collapse
Affiliation(s)
- Aleksey V. Belyaev
- Faculty of Physics, M.V.Lomonosov Moscow State University, 1, Leninskiye Gory, build.2, Moscow, 119991 Russia
| | - Irina V. Fedotova
- Faculty of Physics, M.V.Lomonosov Moscow State University, 1, Leninskiye Gory, build.2, Moscow, 119991 Russia
| |
Collapse
|
|
15
|
Scuderi L, Fragiotta S, Di Pippo M, Abdolrahimzadeh S. The Role of Diabetic Choroidopathy in the Pathogenesis and Progression of Diabetic Retinopathy. Int J Mol Sci 2023; 24:10167. [PMID: 37373315 DOI: 10.3390/ijms241210167] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 06/09/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetic choroidopathy was first described on histopathological specimens of diabetic eyes. This alteration was characterized by the accumulation of PAS-positive material within the intracapillary stroma. Inflammation and polymorphonuclear neutrophils (PMNs) activation are crucial elements in choriocapillaris impairment. The evidence of diabetic choroidopathy in vivo was confirmed with multimodal imaging, which provides key quantitative and qualitative features to characterize the choroidal involvement. The choroid can be virtually affected in each vascular layer, from Haller's layer to the choriocapillaris. However, the damage on the outer retina and photoreceptor cells is essentially driven by a choriocapillaris deficiency, which can be assessed through optical coherence tomography angiography (OCTA). The identification of characteristic features of diabetic choroidopathy can be significant for understanding the potential pathogenic and prognostic implications in diabetic retinopathy.
Collapse
Affiliation(s)
- Luca Scuderi
- Department of Sense Organs, Sapienza University of Rome, 00161 Rome, Italy
| | - Serena Fragiotta
- Ophthalmology Unit, Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Sapienza University of Rome, Via di Grottarossa 1035/1039, 00189 Rome, Italy
- UOC Ophthalmology, Department of Surgical Areas, S.M. Goretti Hospital, 04100 Latina, Italy
| | - Mariachiara Di Pippo
- Ophthalmology Unit, Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Sapienza University of Rome, Via di Grottarossa 1035/1039, 00189 Rome, Italy
| | - Solmaz Abdolrahimzadeh
- Ophthalmology Unit, Neurosciences, Mental Health, and Sensory Organs (NESMOS) Department, Sapienza University of Rome, Via di Grottarossa 1035/1039, 00189 Rome, Italy
- St. Andrea Hospital, Via di Grottarossa 1035/1039, 00189 Rome, Italy
| |
Collapse
|
|
16
|
Beckman JD, DaSilva A, Aronovich E, Nguyen A, Nguyen J, Hargis G, Reynolds D, Vercellotti GM, Betts B, Wood DK. JAK-STAT inhibition reduces endothelial prothrombotic activation and leukocyte-endothelial proadhesive interactions. J Thromb Haemost 2023; 21:1366-1380. [PMID: 36738826 PMCID: PMC10246778 DOI: 10.1016/j.jtha.2023.01.027] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including Bcr-abl-negative myeloproliferative neoplasms (MPNs), graft-vs-host disease, and COVID-19 have been noted to have increased activation of the janus kinase (JAK)-signal transducer and downstream activator of transcription (STAT) pathways. Two notable inhibitors of the JAK-STAT pathway are ruxolitinib (JAK1/2 inhibitor) and fedratinib (JAK2 inhibitor), which are currently used to treat MPN patients. However, in some conditions, it has been noted that JAK inhibitors can increase the risk of thromboembolic complications. OBJECTIVES We sought to define the anti-inflammatory and antithrombotic effects of JAK-STAT inhibitors in vascular endothelial cells. METHODS We assessed endothelial activation in the presence or absence of ruxolitinib or fedratinib by using immunoblots, immunofluorescence, qRT-PCR, and function coagulation assays. Finally, we used endothelialized microfluidics perfused with blood from normal and JAK2V617F+ individuals to evaluate whether ruxolitinib and fedratinib changed cell adhesion. RESULTS We found that both ruxolitinib and fedratinib reduced endothelial cell phospho-STAT1 and STAT3 signaling and attenuated nuclear phospho-NK-κB and phospho-c-Jun localization. JAK-STAT inhibition also limited secretion of proadhesive and procoagulant P-selectin and von Willebrand factor and proinflammatory IL-6. Likewise, we found that JAK-STAT inhibition reduced endothelial tissue factor and urokinase plasminogen activator expression and activity. CONCLUSIONS By using endothelialized microfluidics perfused with whole blood samples, we demonstrated that endothelial treatment with JAK-STAT inhibitors prevented rolling of both healthy control and JAK2V617F MPN leukocytes. Together, these findings demonstrate that JAK-STAT inhibitors reduce the upregulation of critical prothrombotic pathways and prevent increased leukocyte-endothelial adhesion.
Collapse
Affiliation(s)
- Joan D Beckman
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA.
| | - Angelica DaSilva
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - Elena Aronovich
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Aithanh Nguyen
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Julia Nguyen
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Geneva Hargis
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| | - David Reynolds
- Department of Biomedical Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Gregory M Vercellotti
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - Brian Betts
- Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
| | - David K Wood
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
17
|
Li Z, Dong S, Huang S, Sun Y, Sun Y, Zhao B, Qi Q, Xiong L, Hong F, Jiang Y. Role of CD34 in inflammatory bowel disease. Front Physiol 2023; 14:1144980. [PMID: 37051017 PMCID: PMC10083274 DOI: 10.3389/fphys.2023.1144980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/15/2023] [Indexed: 03/29/2023] Open
Abstract
Inflammatory bowel disease (IBD) is caused by a variety of pathogenic factors, including chronic recurrent inflammation of the ileum, rectum, and colon. Immune cells and adhesion molecules play an important role in the course of the disease, which is actually an autoimmune disease. During IBD, CD34 is involved in mediating the migration of a variety of immune cells (neutrophils, eosinophils, and mast cells) to the inflammatory site, and its interaction with various adhesion molecules is involved in the occurrence and development of IBD. Although the function of CD34 as a partial cell marker is well known, little is known on its role in IBD. Therefore, this article describes the structure and biological function of CD34, as well as on its potential mechanism in the development of IBD.
Collapse
Affiliation(s)
- Zhiyuan Li
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Shuyan Dong
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
| | - Shichen Huang
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Yuhan Sun
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Yingzhi Sun
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
| | - Beibei Zhao
- School of Pharmacy, Wannan Medical College, Wuhu, Anhui, China
| | - Qiulan Qi
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
| | - Lei Xiong
- Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Yuxin Jiang, ; Feng Hong, ; Lei Xiong,
| | - Feng Hong
- The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
- *Correspondence: Yuxin Jiang, ; Feng Hong, ; Lei Xiong,
| | - Yuxin Jiang
- Jiaxing Key Laboratory of Virus-Related Infectious Diseases, The Affiliated Hospital of Jiaxing University, Jiaxing University College of Medicine, Jiaxing, Zhejiang, China
- *Correspondence: Yuxin Jiang, ; Feng Hong, ; Lei Xiong,
| |
Collapse
|
|
18
|
Baby S, Reljic T, Villalba N, Kumar A, Yuan SY. Endothelial glycocalyx-associated molecules as potential serological markers for sepsis-associated encephalopathy: A systematic review and meta-analysis. PLoS One 2023; 18:e0281941. [PMID: 36802387 PMCID: PMC9942976 DOI: 10.1371/journal.pone.0281941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 02/03/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Sepsis-associated encephalopathy (SAE) is characterized by a diffuse cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system infection. The endothelial glycocalyx is a dynamic mesh containing heparan sulfate linked to proteoglycans and glycoproteins, including selectins and vascular/intercellular adhesion molecules (V/I-CAMs), which protects the endothelium while mediating mechano-signal transduction between the blood and vascular wall. During severe inflammatory states, components of the glycocalyx are shed into the circulation and can be detected in soluble forms. Currently, SAE remains a diagnosis of exclusion and limited information is available on the utility of glycocalyx-associated molecules as biomarkers for SAE. We set out to synthesize all available evidence on the association between circulating molecules released from the endothelial glycocalyx surface during sepsis and sepsis-associated encephalopathy. METHODS MEDLINE (PubMed) and EMBASE were searched since inception until May 2, 2022 to identify eligible studies. Any comparative observational study: i) evaluating the association between sepsis and cognitive decline and ii) providing information on level of circulating glycocalyx-associated molecules was eligible for inclusion. RESULTS Four case-control studies with 160 patients met the inclusion criteria. Meta-analysis of biomarkers ICAM-1 (SMD 0.41; 95% CI 0.05-0.76; p = 0.03; I2 = 50%) and VCAM-1 (SMD 0.55; 95% CI 0.12-0.98; p = 0.01; I2 = 82%) revealed higher pooled mean concentration in patients with SAE compared to the patients with sepsis alone. Single studies reported elevated levels of P-selectin (MD 0.80; 95% CI -17.77-19.37), E-selectin (MD 96.40; 95% Cl 37.90-154.90), heparan sulfate NS2S (MD 19.41; 95% CI 13.37-25.46), and heparan sulfate NS+NS2S+NS6S (MD 67.00; 95% CI 31.00-103.00) in patients with SAE compared to the patients with sepsis alone. CONCLUSION Plasma glycocalyx-associated molecules are elevated in SAE and may be useful for early identification of cognitive decline in sepsis patients.
Collapse
Affiliation(s)
- Sheon Baby
- Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America
| | - Tea Reljic
- Department of Evidence Based Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America
| | - Nuria Villalba
- Department of Molecular Pharmacology & Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America
| | - Ambuj Kumar
- Department of Evidence Based Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America
| | - Sarah Y. Yuan
- Department of Molecular Pharmacology & Physiology, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, United States of America
| |
Collapse
|
|
19
|
Zundler S, Schulze LL, Neurath MF. Controlling in and out - the future of interfering with immune cell trafficking in inflammatory bowel disease. Expert Rev Clin Immunol 2023; 19:155-167. [PMID: 36427088 DOI: 10.1080/1744666x.2023.2152794] [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: 11/27/2022]
Abstract
INTRODUCTION Immune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease. AREAS COVERED In this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets. EXPERT OPINION Finally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.
Collapse
Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
20
|
Sy SKB, Tanaka C, Grosch K. Population Pharmacokinetics and Pharmacodynamics of Crizanlizumab in Healthy Subjects and Patients with Sickle Cell Disease. Clin Pharmacokinet 2023; 62:249-266. [PMID: 36529836 DOI: 10.1007/s40262-022-01193-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Crizanlizumab is a humanized monoclonal antibody against P-selectin for the prevention of vaso-occlusive crises in sickle cell disease (SCD). The objective of this study was to investigate crizanlizumab population pharmacokinetics (PK) and pharmacodynamics (PD), as well as influential covariates. METHODS A population PK model for crizanlizumab was developed from healthy volunteer and SCD patient data, using a two-compartment intravenous infusion model utilizing a target-mediated drug disposition (TMDD) approach. The relationship between crizanlizumab concentration and ex vivo P-selectin inhibition was fitted to a non-linear sigmoidal Emax model. Covariate selection was performed in a stepwise manner. RESULTS Crizanlizumab exhibits nonlinear pharmacokinetics in the wide dose range of 0.2-8 mg/kg body weight. The population pharmacokinetic base model incorporated body weight as covariate in the form of allometric scaling wherein the exponents were fixed to 0.8. SCD patients had higher baseline soluble P-selectin concentration, resulting in a higher estimated initial target concentration. The typical individual in the model is a 70 kg SCD patient with normal renal function and a baseline albumin of 43 g/L; CL was 0.012 L/h while Vss was 5.2 L. For the population PD model, none of the identified additional factors beyond PD assay and covariates, such as body weight at baseline nor patient type differences, led to relevant differences in P-selectin % inhibition. CONCLUSIONS Renal and hepatic impairments, concomitant hydroxyurea usage, and presence of anti-drug antibody are not expected to impact the exposure of crizanlizumab. The model allows for extrapolating the PK of crizanlizumab to pediatric population and evaluation of alternative regimens and route of administration. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: SUSTAIN (CSEG101A2201 Phase 2), ClinicalTrials.gov identifier: NCT01895361 [10 July 2013]; CSEG101A2202 (Phase 2), ClinicalTrials.gov identifier: NCT03264989 [29 August 2017].
Collapse
Affiliation(s)
- Sherwin K B Sy
- Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA.
| | - Chiaki Tanaka
- Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA
| | - Kai Grosch
- Novartis Pharma AG, Forum 1, Novartis Campus, 4056, Basel, Switzerland
| |
Collapse
|
|
21
|
Gonzalez-Gil A, Schnaar RL. Glycans in Inflammation. ENCYCLOPEDIA OF CELL BIOLOGY 2023:338-348. [DOI: 10.1016/b978-0-12-821618-7.00007-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
22
|
Abi Rached NM, Gbotosho OT, Archer DR, Jones JA, Sterling MS, Hyacinth HI. Adhesion molecules and cerebral microvascular hemodynamic abnormalities in sickle cell disease. Front Neurol 2022; 13:976063. [PMID: 36570439 PMCID: PMC9767957 DOI: 10.3389/fneur.2022.976063] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Cerebrovascular abnormalities are a common feature of sickle cell disease that may be associated with risk of vaso-occlusive pain crises, microinfarcts, and cognitive impairment. An activated endothelium and adhesion factors, VCAM-1 and P-selectin, are implicated in sickle cell vasculopathy, including abnormal hemodynamics and leukocyte adherence. This study examined the association between cerebral expression of these adhesion factors and cortical microvascular blood flow dynamics by using in-vivo two-photon microscopy. We also examined the impact of blood transfusion treatment on these markers of vasculopathy. Results showed that sickle cell mice had significantly higher maximum red blood cell (RBC) velocity (6.80 ± 0.25 mm/sec, p ≤ 0.01 vs. 5.35 ± 0.35 mm/sec) and more frequent blood flow reversals (18.04 ± 0.95 /min, p ≤ 0.01 vs. 13.59 ± 1.40 /min) in the cortical microvasculature compared to controls. In addition, sickle cell mice had a 2.6-fold (RFU/mm2) increase in expression of VCAM-1 and 17-fold (RFU/mm2) increase in expression of P-selectin compared to controls. This was accompanied by an increased frequency in leukocyte adherence (4.83 ± 0.57 /100 μm/min vs. 2.26 ± 0.37 /100 μm/min, p ≤ 0.001). We also found that microinfarcts identified in sickle cell mice were 50% larger than in controls. After blood transfusion, many of these parameters improved, as results demonstrated that sickle cell mice had a lower post-transfusion maximum RBC velocity (8.30 ± 0.98 mm/sec vs. 11.29 ± 0.95 mm/sec), lower frequency of blood flow reversals (12.80 ± 2.76 /min vs. 27.75 ± 2.09 /min), and fewer instances of leukocyte adherence compared to their pre-transfusion imaging time point (1.35 ± 0.32 /100 μm/min vs. 3.46 ± 0.58 /100 μm/min). Additionally, we found that blood transfusion was associated with lower expression of adhesion factors. Our results suggest that blood transfusion and adhesion factors, VCAM-1 and P-selectin, are potential therapeutic targets for addressing cerebrovascular pathology, such as vaso-occlusion, in sickle cell disease.
Collapse
Affiliation(s)
- Noor Mary Abi Rached
- Neuroscience and Behavioral Biology Undergraduate Program, Emory University, Atlanta, GA, United States
| | - Oluwabukola T. Gbotosho
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - David R. Archer
- Aflac Cancer and Blood Disorders Center, Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Jayre A. Jones
- Aflac Cancer and Blood Disorders Center, Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Morgan S. Sterling
- Aflac Cancer and Blood Disorders Center, Emory University Department of Pediatrics and Children's Healthcare of Atlanta, Atlanta, GA, United States
| | - Hyacinth I. Hyacinth
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| |
Collapse
|
|
23
|
Abd Wahab MA, Mohd Yusof E, Ahmad R, Salleh MZ, Teh LK. Peri-implant Bone Healing: Its Basic Osteogenesis and Biomarkers. NOVEMBER ISSUE 2022; 18:324-331. [DOI: 10.47836/mjmhs.18.6.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Abstract
The continuous sequence of bone healing phases starts off with osteoconduction to the implant surface, depending on the migration of osteogenic cells. Osteoneogenesis ensues resulting in a mineralised interfacial matrix and is followed by bone remodelling to the implant interface at discrete sites. Dental implant drilling procedure and placement produce osseous defect which is filled by blood. Within seconds, blood proteins are adsorbed onto the implant surface and platelets are activated resulting in the release of cytokines and growth factors. Further platelet aggregation initiates osteoconduction to the surface, followed by osteoneogenesis, forming an extracellular matrix. Subsequently, remodelling creates a bone to implant interface which can be explained through distance and contact osteogenesis. The dental implant surface has been shown to influence osteoconduction by modifying protein properties and adsorption around the implant. Salivary biomarkers may be considered as a specific and sensitive diagnostic tool to detect these changes in protein expressions after implant placement. Thus, the purpose of this narrative review is to provide a detailed account of the bone healing mechanism associated with dental implant placement, as well as how the implant surface architecture and protein release play a role in bone healing, and the potential use of saliva to detect these biomarkers.
Collapse
|
|
24
|
Liu W, Cronin CG, Cao Z, Wang C, Ruan J, Pulikkot S, Hall A, Sun H, Groisman A, Chen Y, Vella AT, Hu L, Liang BT, Fan Z. Nexinhib20 Inhibits Neutrophil Adhesion and β 2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1574-1585. [PMID: 36165184 PMCID: PMC9529951 DOI: 10.4049/jimmunol.2101112] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 08/03/2022] [Indexed: 11/07/2022]
Abstract
Neutrophils are critical for mediating inflammatory responses. Inhibiting neutrophil recruitment is an attractive approach for preventing inflammatory injuries, including myocardial ischemia-reperfusion (I/R) injury, which exacerbates cardiomyocyte death after primary percutaneous coronary intervention in acute myocardial infarction. In this study, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits not only exocytosis but also neutrophil adhesion by limiting β2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8-induced β2 integrin-dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β2 integrin activation after IL-8 stimulation. Western blots of Ras-related C3 botulinum toxin substrate 1 (Rac-1)-GTP pull-down assays confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. An in vitro competition assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.
Collapse
Affiliation(s)
- Wei Liu
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Chunxia G Cronin
- Pat and Jim Calhoun Cardiology Center, School of Medicine, UConn Health, Farmington, CT
| | - Ziming Cao
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Chengliang Wang
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Jianbin Ruan
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Sunitha Pulikkot
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Alexxus Hall
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Hao Sun
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Alex Groisman
- Department of Physics, University of California San Diego, La Jolla, CA
| | - Yunfeng Chen
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX
- Department of Pathology, University of Texas Medical Branch, Galveston, TX
| | - Anthony T Vella
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Liang Hu
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; and
| | - Bruce T Liang
- Pat and Jim Calhoun Cardiology Center, School of Medicine, UConn Health, Farmington, CT;
| | - Zhichao Fan
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT;
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA
| |
Collapse
|
|
25
|
Tian Y, Seeto WJ, Páez-Arias MA, Hahn MS, Lipke EA. Endothelial colony forming cell rolling and adhesion supported by peptide-grafted hydrogels. Acta Biomater 2022; 152:74-85. [PMID: 36031035 DOI: 10.1016/j.actbio.2022.08.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 07/28/2022] [Accepted: 08/22/2022] [Indexed: 01/13/2023]
Abstract
The aim of this study was to investigate the ability of peptides and peptide combinations to support circulating endothelial colony forming cell (ECFC) rolling and adhesion under shear flow, informing biomaterial design in moving toward rapid cardiovascular device endothelialization. ECFCs have high proliferative capability and can differentiate into endothelial cells, making them a promising cell source for endothelialization. Both single peptides and peptide combinations designed to target integrins α4β1 and α5β1 were coupled to poly(ethylene glycol) hydrogels, and their performance was evaluated by monitoring velocity patterns during the ECFC rolling process, in addition to firm adhesion (capture). Tether percentage and velocity fluctuation, a parameter newly defined here, were found to be valuable in assessing cell rolling velocity patterns and when used in combination were able to predict cell capture. REDV-containing peptides binding integrin α4β1 have been previously shown to reduce ECFC rolling velocity but not to support firm adhesion. This study finds that the performance of REDV-containing peptides in facilitating ECFC dynamic adhesion and capture can be improved by combination with α5β1 integrin-binding peptides, which support ECFC static adhesion. Moreover, when similar in length, the peptide combinations may have synergistic effects in capturing ECFCs. With matching lengths, the peptide combinations including CRRETAWAC(cyclic)+REDV, P_RGDS+KSSP_REDV, and P_RGDS+P_REDV showed high values in both tether percentage and velocity fluctuation and improvement in ECFC capture compared to the single peptides at the shear rate of 20 s-1. These newly identified peptide combinations have the potential to be used as vascular device coatings to recruit ECFCs. STATEMENT OF SIGNIFICANCE: Restoration of functional endothelium following placement of stents and vascular grafts is critical for maintaining long-term patency. Endothelial colony forming cells (ECFCs) circulating in blood flow are a valuable cell source for rapid endothelialization. Here we identify and test novel peptides and peptide combinations that can potentially be used as coatings for vascular devices to support rolling and capture of ECFCs from flow. In addition to the widely used assessment of final ECFC adhesion, we also recorded the rolling process to quantitatively evaluate the interaction between ECFCs and the peptides, obtaining detailed performance of the peptides and gaining insight into effective capture molecule design. Peptide combinations targeting both integrin α4β1 and integrin α5β1 showed the highest percentages of ECFC capture.
Collapse
Affiliation(s)
- Yuan Tian
- Department of Chemical Engineering, Auburn University, 212 Ross Hall, Auburn, AL, 36849, USA
| | - Wen J Seeto
- Department of Chemical Engineering, Auburn University, 212 Ross Hall, Auburn, AL, 36849, USA
| | - Mayra A Páez-Arias
- Department of Chemical Engineering, Auburn University, 212 Ross Hall, Auburn, AL, 36849, USA
| | - Mariah S Hahn
- Biomedical Engineering Department, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA
| | - Elizabeth A Lipke
- Department of Chemical Engineering, Auburn University, 212 Ross Hall, Auburn, AL, 36849, USA.
| |
Collapse
|
|
26
|
Fu P, Li P, Hu Y. A general numerical model of leukocyte adhesion in microchannels. INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING 2022; 38:e3606. [PMID: 35488511 DOI: 10.1002/cnm.3606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 03/11/2022] [Accepted: 04/19/2022] [Indexed: 06/14/2023]
Abstract
Leukocyte adhesion on the vascular endothelium plays an important role in human immune system and reflects the physiological condition of a human body. In this paper, a generally implementable dynamic adhesion model based on the length limit of microvilli was developed to explore the behavior of a suspended leukocyte's adhesion process under microchannel shear flow. Simulations showed that the whole adhesion process can be divided into cell sedimentation, preliminary adhesion and stable dynamic adhesion stages. The cell tumbling kinetics, cell deformation, cell adhesion area and adhesion force were studied under the conditions of various bond strength, cell membrane surface tension, inlet flow velocity and cytoplasmic viscosity. Results showed that the bond strength affects the cell tumbling behaviors differently by changing the adhesion force. The cell with lower membrane surface tension induces a larger adhesion area, and eventually results in a greater adhesion and a lower cell tumbling velocity. The flow velocity changes cell velocity through the flow viscous force during the whole adhesion process. The cytoplasmic viscosity affects adhesion mainly in the preliminary adhesion stage by changing the cell deformation rate but has slight effect on the stabilized dynamic adhesion on cells. This study provides a simple theoretical basis to further clarify the mechanism of cell behaviors under stress and adhesion and becomes one of the prerequisites for study of tissue inflammation, wound healing, and disease treatments.
Collapse
Affiliation(s)
- Peixin Fu
- State Key Laboratory of Ocean Engineering, School of Naval Architecture, Ocean and Civil Engineering, Collaborative Innovation Center for Advanced Ship and Deep-Sea Exploration, Shanghai Jiao Tong University, Shanghai, China
| | - Peiye Li
- State Key Laboratory of Ocean Engineering, School of Naval Architecture, Ocean and Civil Engineering, Collaborative Innovation Center for Advanced Ship and Deep-Sea Exploration, Shanghai Jiao Tong University, Shanghai, China
| | - Yandong Hu
- State Key Laboratory of Ocean Engineering, School of Naval Architecture, Ocean and Civil Engineering, Collaborative Innovation Center for Advanced Ship and Deep-Sea Exploration, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
27
|
Margraf A, Lowell CA, Zarbock A. Neutrophils in acute inflammation: current concepts and translational implications. Blood 2022; 139:2130-2144. [PMID: 34624098 PMCID: PMC9728535 DOI: 10.1182/blood.2021012295] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 10/05/2021] [Indexed: 12/14/2022] Open
Abstract
Modulation of neutrophil recruitment and function is crucial for targeting inflammatory cells to sites of infection to combat invading pathogens while, at the same time, limiting host tissue injury or autoimmunity. The underlying mechanisms regulating recruitment of neutrophils, 1 of the most abundant inflammatory cells, have gained increasing interest over the years. The previously described classical recruitment cascade of leukocytes has been extended to include capturing, rolling, adhesion, crawling, and transmigration, as well as a reverse-transmigration step that is crucial for balancing immune defense and control of remote organ endothelial leakage. Current developments in the field emphasize the importance of cellular interplay, tissue environmental cues, circadian rhythmicity, detection of neutrophil phenotypes, differential chemokine sensing, and contribution of distinct signaling components to receptor activation and integrin conformations. The use of therapeutics modulating neutrophil activation responses, as well as mutations causing dysfunctional neutrophil receptors and impaired signaling cascades, have been defined in translational animal models. Human correlates of such mutations result in increased susceptibility to infections or organ damage. This review focuses on current advances in the understanding of the regulation of neutrophil recruitment and functionality and translational implications of current discoveries in the field with a focus on acute inflammation and sepsis.
Collapse
Affiliation(s)
- Andreas Margraf
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany
- William Harvey Research Institute, Bart's and the London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Clifford A. Lowell
- Department of Laboratory Medicine, University of California, San Francisco
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Muenster, Germany
| |
Collapse
|
|
28
|
Walter LO, Cardoso CC, Santos‐Pirath ÍM, Costa HZ, Gartner R, Werle I, Mohr ETB, da Rosa JS, Felisberto M, Kretzer IF, Masukawa II, Vanny PDA, Luiz MC, de Moraes ACR, Dalmarco EM, Santos‐Silva MC. The relationship between peripheral immune response and disease severity in SARS-CoV-2-infected subjects: A cross-sectional study. Immunology 2022; 165:481-496. [PMID: 35146763 PMCID: PMC9111570 DOI: 10.1111/imm.13457] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/21/2022] [Accepted: 01/31/2022] [Indexed: 11/30/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and marked by an intense inflammatory response and immune dysregulation in the most severe cases. In order to better clarify the relationship between peripheral immune system changes and the severity of COVID-19, this study aimed to evaluate the frequencies and absolute numbers of peripheral subsets of neutrophils, monocytes, and dendritic cells (DCs), in addition to quantifying the levels of inflammatory mediators. One hundred fifty-seven COVID-19 patients were stratified into mild, moderate, severe, and critical disease categories. The cellular components and circulating cytokines were assessed by flow cytometry. Nitric oxide (NOx) and myeloperoxidase (MPO) levels were measured by colourimetric tests. COVID-19 patients presented neutrophilia, with signs of emergency myelopoiesis. Alterations in the monocytic component were observed in patients with moderate to critical illness, with an increase in classical monocytes and a reduction in nonclassical monocytes, in addition to a reduction in the expression of HLA-DR in all subtypes of monocytes, indicating immunosuppression. DCs, especially plasmacytoid DCs, also showed a large reduction in moderate to critical patients. COVID-19 patients showed an increase in MPO, interleukin (IL)-12, IL-6, IL-10, and IL-8, accompanied by a reduction in IL-17A and NOx. IL-10 levels ≥14 pg/ml were strongly related to the worst outcome, with a sensitivity of 78·3% and a specificity of 79·1%. The results of this study indicate the presence of systemic effects induced by COVID-19, which appear to be related to the pathophysiology of the disease, highlighting the potential of IL-10 as a possible prognostic biomarker for COVID-19.
Collapse
Affiliation(s)
- Laura Otto Walter
- Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Chandra Chiappin Cardoso
- Division of Clinical AnalysisFlow Cytometry ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Íris Mattos Santos‐Pirath
- Division of Clinical AnalysisFlow Cytometry ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Heloisa Zorzi Costa
- Division of Clinical AnalysisFlow Cytometry ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Rafaela Gartner
- Clinical Analysis DepartmentHealth Sciences Center, Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Isabel Werle
- Clinical Analysis DepartmentHealth Sciences Center, Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | | | - Julia Salvan da Rosa
- Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Mariano Felisberto
- Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Iara Fabricia Kretzer
- Clinical Analysis DepartmentHealth Sciences Center, Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Ivete Ioshiko Masukawa
- Infectious Disease ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
- Infectious Disease ServiceNereu Ramos Hospital. State Health DepartmentFlorianópolisSanta CatarinaBrazil
| | - Patrícia de Almeida Vanny
- Infectious Disease ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Magali Chaves Luiz
- Infectious Disease ServiceNereu Ramos Hospital. State Health DepartmentFlorianópolisSanta CatarinaBrazil
| | - Ana Carolina Rabello de Moraes
- Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
- Division of Clinical AnalysisFlow Cytometry ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Eduardo Monguilhott Dalmarco
- Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
- Division of Clinical AnalysisFlow Cytometry ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| | - Maria Cláudia Santos‐Silva
- Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
- Division of Clinical AnalysisFlow Cytometry ServiceUniversity Hospital of the Federal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
- Clinical Analysis DepartmentHealth Sciences Center, Postgraduate Program in PharmacyFederal University of Santa CatarinaFlorianópolisSanta CatarinaBrazil
| |
Collapse
|
|
29
|
Gonzalez RJ, von Andrian UH. Quo vadis, neutrophil? Cell 2022; 185:759-761. [PMID: 35245478 DOI: 10.1016/j.cell.2022.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/07/2022] [Accepted: 02/07/2022] [Indexed: 01/13/2023]
Abstract
Neutrophil recruitment from blood into tissues is a hallmark of inflammation and anti-microbial host defense. In this issue, De Giovanni et al. describe an unanticipated role for a serotonin metabolite, 5-HIAA, which is produced by activated platelets and mast cells and engages the orphan receptor, GPR35, to recruit neutrophils to inflamed tissues.
Collapse
Affiliation(s)
- Rodrigo J Gonzalez
- Department of Immunology, Harvard Medical School, Boston, MA, USA; The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Ulrich H von Andrian
- Department of Immunology, Harvard Medical School, Boston, MA, USA; The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
| |
Collapse
|
|
30
|
Brown FCW, Hill JA, Pedlar CR. Compression Garments for Recovery from Muscle Damage: Evidence and Implications of Dose Responses. Curr Sports Med Rep 2022; 21:45-52. [PMID: 35120050 DOI: 10.1249/jsr.0000000000000933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
ABSTRACT The use of compression garments (CG) has been associated with improved recovery following exercise-induced muscle damage. The mechanisms responsible are not well established, and no consensus exists regarding the effects of compression pressure (i.e., the "dose"), which until recently was seldom reported. With the increasing prevalence of studies reporting directly measured pressures, the present review aims to consolidate current evidence on optimal pressures for recovery from exercise-induced muscle damage. In addition, recent findings suggesting that custom-fitted garments provide greater precision and experimental control are discussed. Finally, biochemical data from human trials are presented to support a theoretical mechanism by which CG enhance recovery, with recommendations for future research. The effects of compression on adaptation remain unexplored. More studies are required to investigate the relationship between compression pressure and the recovery of performance and physiological outcomes. Furthermore, improved mechanistic understanding may help elucidate the optimal conditions by which CG enhance recovery.
Collapse
Affiliation(s)
| | - Jessica A Hill
- Faculty of Sport, Health and Applied Science, St. Mary's University, Twickenham, United Kingdom
| | | |
Collapse
|
|
31
|
Steiger S, Rossaint J, Zarbock A, Anders HJ. Secondary Immunodeficiency Related to Kidney Disease (SIDKD)-Definition, Unmet Need, and Mechanisms. J Am Soc Nephrol 2022; 33:259-278. [PMID: 34907031 PMCID: PMC8819985 DOI: 10.1681/asn.2021091257] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Kidney disease is a known risk factor for poor outcomes of COVID-19 and many other serious infections. Conversely, infection is the second most common cause of death in patients with kidney disease. However, little is known about the underlying secondary immunodeficiency related to kidney disease (SIDKD). In contrast to cardiovascular disease related to kidney disease, which has triggered countless epidemiologic, clinical, and experimental research activities or interventional trials, investments in tracing, understanding, and therapeutically targeting SIDKD have been sparse. As a call for more awareness of SIDKD as an imminent unmet medical need that requires rigorous research activities at all levels, we review the epidemiology of SIDKD and the numerous aspects of the abnormal immunophenotype of patients with kidney disease. We propose a definition of SIDKD and discuss the pathogenic mechanisms of SIDKD known thus far, including more recent insights into the unexpected immunoregulatory roles of elevated levels of FGF23 and hyperuricemia and shifts in the secretome of the intestinal microbiota in kidney disease. As an ultimate goal, we should aim to develop therapeutics that can reduce mortality due to infections in patients with kidney disease by normalizing host defense to pathogens and immune responses to vaccines.
Collapse
Affiliation(s)
- Stefanie Steiger
- Division of Nephrology, Department of Medicine IV, Ludwig Maximilians University Hospital of Munich, Munich, Germany
| | - Jan Rossaint
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Ludwig Maximilians University Hospital of Munich, Munich, Germany
| |
Collapse
|
|
32
|
Bongrand P. Is There a Need for a More Precise Description of Biomolecule Interactions to Understand Cell Function? Curr Issues Mol Biol 2022; 44:505-525. [PMID: 35723321 PMCID: PMC8929073 DOI: 10.3390/cimb44020035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/15/2022] [Accepted: 01/17/2022] [Indexed: 11/16/2022] Open
Abstract
An important goal of biological research is to explain and hopefully predict cell behavior from the molecular properties of cellular components. Accordingly, much work was done to build extensive “omic” datasets and develop theoretical methods, including computer simulation and network analysis to process as quantitatively as possible the parameters contained in these resources. Furthermore, substantial effort was made to standardize data presentation and make experimental results accessible to data scientists. However, the power and complexity of current experimental and theoretical tools make it more and more difficult to assess the capacity of gathered parameters to support optimal progress in our understanding of cell function. The purpose of this review is to focus on biomolecule interactions, the interactome, as a specific and important example, and examine the limitations of the explanatory and predictive power of parameters that are considered as suitable descriptors of molecular interactions. Recent experimental studies on important cell functions, such as adhesion and processing of environmental cues for decision-making, support the suggestion that it should be rewarding to complement standard binding properties such as affinity and kinetic constants, or even force dependence, with less frequently used parameters such as conformational flexibility or size of binding molecules.
Collapse
Affiliation(s)
- Pierre Bongrand
- Lab Adhesion and Inflammation (LAI), Inserm UMR 1067, Cnrs UMR 7333, Aix-Marseille Université UM 61, Marseille 13009, France
| |
Collapse
|
|
33
|
Law HL, Cooper D. Methods for Assessing the Effects of Galectins on Leukocyte Trafficking and Clearance. Methods Mol Biol 2022; 2442:581-601. [PMID: 35320547 DOI: 10.1007/978-1-0716-2055-7_31] [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] [Indexed: 06/14/2023]
Abstract
Numerous protocols exist for investigating leukocyte recruitment and clearance both in vitro and in vivo. Here we describe an in vitro flow chamber assay typically used for studying the mechanisms underpinning leukocyte movement through the endothelium and zymosan-induced peritonitis, an acute in vivo model of inflammation that enables both leukocyte trafficking and clearance to be monitored. Insight is given as to how these models can be used to study the actions of galectins on the inflammatory process.
Collapse
Affiliation(s)
- Hannah L Law
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
| | - Dianne Cooper
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
| |
Collapse
|
|
34
|
Puech PH, Bongrand P. Mechanotransduction as a major driver of cell behaviour: mechanisms, and relevance to cell organization and future research. Open Biol 2021; 11:210256. [PMID: 34753321 PMCID: PMC8586914 DOI: 10.1098/rsob.210256] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 01/04/2023] Open
Abstract
How do cells process environmental cues to make decisions? This simple question is still generating much experimental and theoretical work, at the border of physics, chemistry and biology, with strong implications in medicine. The purpose of mechanobiology is to understand how biochemical and physical cues are turned into signals through mechanotransduction. Here, we review recent evidence showing that (i) mechanotransduction plays a major role in triggering signalling cascades following cell-neighbourhood interaction; (ii) the cell capacity to continually generate forces, and biomolecule properties to undergo conformational changes in response to piconewton forces, provide a molecular basis for understanding mechanotransduction; and (iii) mechanotransduction shapes the guidance cues retrieved by living cells and the information flow they generate. This includes the temporal and spatial properties of intracellular signalling cascades. In conclusion, it is suggested that the described concepts may provide guidelines to define experimentally accessible parameters to describe cell structure and dynamics, as a prerequisite to take advantage of recent progress in high-throughput data gathering, computer simulation and artificial intelligence, in order to build a workable, hopefully predictive, account of cell signalling networks.
Collapse
Affiliation(s)
- Pierre-Henri Puech
- Lab Adhesion and Inflammation (LAI), Inserm UMR 1067, CNRS UMR 7333, Aix-Marseille Université UM61, Marseille, France
| | - Pierre Bongrand
- Lab Adhesion and Inflammation (LAI), Inserm UMR 1067, CNRS UMR 7333, Aix-Marseille Université UM61, Marseille, France
| |
Collapse
|
|
35
|
Singh K, Hotchkiss KM, Patel KK, Wilkinson DS, Mohan AA, Cook SL, Sampson JH. Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma. Cancers (Basel) 2021; 13:5367. [PMID: 34771532 PMCID: PMC8582389 DOI: 10.3390/cancers13215367] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 12/12/2022] Open
Abstract
Glioblastoma is an immunologically 'cold' tumor, which are characterized by absent or minimal numbers of tumor-infiltrating lymphocytes (TILs). For those tumors that have been invaded by lymphocytes, they are profoundly exhausted and ineffective. While many immunotherapy approaches seek to reinvigorate immune cells at the tumor, this requires TILs to be present. Therefore, to unleash the full potential of immunotherapy in glioblastoma, the trafficking of lymphocytes to the tumor is highly desirable. However, the process of T cell recruitment into the central nervous system (CNS) is tightly regulated. Naïve T cells may undergo an initial licensing process to enter the migratory phenotype necessary to enter the CNS. T cells then must express appropriate integrins and selectin ligands to interact with transmembrane proteins at the blood-brain barrier (BBB). Finally, they must interact with antigen-presenting cells and undergo further licensing to enter the parenchyma. These T cells must then navigate the tumor microenvironment, which is rich in immunosuppressive factors. Altered tumoral metabolism also interferes with T cell motility. In this review, we will describe these processes and their mediators, along with potential therapeutic approaches to enhance trafficking. We also discuss safety considerations for such approaches as well as potential counteragents.
Collapse
Affiliation(s)
- Kirit Singh
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA; (K.M.H.); (K.K.P.); (D.S.W.); (A.A.M.); (S.L.C.)
| | | | | | | | | | | | - John H. Sampson
- Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA; (K.M.H.); (K.K.P.); (D.S.W.); (A.A.M.); (S.L.C.)
| |
Collapse
|
|
36
|
A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond. Cancers (Basel) 2021; 13:cancers13215331. [PMID: 34771495 PMCID: PMC8582456 DOI: 10.3390/cancers13215331] [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: 09/14/2021] [Revised: 10/18/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Neutrophils are critical immune cells in host defense and maintenance of tissue homeostasis. Studying the complex and diverse functions of these innate immune cells requires a comprehensive toolkit of experimental techniques to elucidate the function and regulation of neutrophils in health and disease. In this review, we discuss key methodologies and their applications in neutrophil research, including in vivo imaging, ex vivo functional assays, and high dimensional single-cell technologies, and how they can be integrated into a multi-modal approach to study neutrophil function in cancer and other diseases. Abstract As key effector cells of the innate immune response, neutrophils are rapidly deployed to sites of inflammation where they deliver a payload of potent effector mechanisms that are essential for host defense against pathogens as well as tissue homeostasis. In addition, neutrophils are central contributors to the pathogenesis of a vast spectrum of inflammatory, degenerative, and neoplastic diseases. As our understanding of neutrophils in health and disease continually expands, so too does our appreciation of their complex and dynamic nature in vivo; from development, maturation, and trafficking to cellular heterogeneity and functional plasticity. Therefore, contemporary neutrophil research relies on multiple complementary methodologies to perform integrated analysis of neutrophil phenotypic heterogeneity, organ- and stimulus-specific trafficking mechanisms, as well as tailored effector functions in vivo. This review discusses established and emerging technologies used to study neutrophils, with a focus on in vivo imaging in animal models, as well as next-generation ex vivo model systems to study mechanisms of neutrophil function. Furthermore, we discuss how high-dimensional single-cell analysis technologies are driving a renaissance in neutrophil biology by redefining our understanding of neutrophil development, heterogeneity, and functional plasticity. Finally, we discuss innovative applications and emerging opportunities to integrate these high-dimensional, multi-modal techniques to deepen our understanding of neutrophils in cancer research and beyond.
Collapse
|
|
37
|
Segura J, He B, Ireland J, Zou Z, Shen T, Roth G, Sun PD. The Role of L-Selectin in HIV Infection. Front Microbiol 2021; 12:725741. [PMID: 34659153 PMCID: PMC8511817 DOI: 10.3389/fmicb.2021.725741] [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: 06/15/2021] [Accepted: 08/27/2021] [Indexed: 11/20/2022] Open
Abstract
HIV envelope glycoprotein is the most heavily glycosylated viral protein complex identified with over 20 glycans on its surface. This glycan canopy is thought to primarily shield the virus from host immune recognition as glycans are poor immunogens in general, however rare HIV neutralizing antibodies nevertheless potently recognize the glycan epitopes. While CD4 and chemokine receptors have been known as viral entry receptor and coreceptor, for many years the role of viral glycans in HIV entry was controversial. Recently, we showed that HIV envelope glycan binds to L-selectin in solution and on CD4 T lymphocytes. The viral glycan and L-selectin interaction functions to facilitate the viral adhesion and entry. Upon entry, infected CD4 T lymphocytes are stimulated to progressively shed L-selectin and suppressing this lectin receptor shedding greatly reduced HIV viral release and caused aggregation of diminutive virus-like particles within experimental infections and from infected primary T lymphocytes derived from both viremic and aviremic individuals. As shedding of L-selectin is mediated by ADAM metalloproteinases downstream of host-cell stimulation, these findings showed a novel mechanism for HIV viral release and offer a potential new class of anti-HIV compounds.
Collapse
Affiliation(s)
- Jason Segura
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Biao He
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Joanna Ireland
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Zhongcheng Zou
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Thomas Shen
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Gwynne Roth
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Peter D Sun
- Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| |
Collapse
|
|
38
|
Biomechanics of Neutrophil Tethers. Life (Basel) 2021; 11:life11060515. [PMID: 34073130 PMCID: PMC8230032 DOI: 10.3390/life11060515] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/11/2022] Open
Abstract
Leukocytes, including neutrophils, propelled by blood flow, can roll on inflamed endothelium using transient bonds between selectins and their ligands, and integrins and their ligands. When such receptor–ligand bonds last long enough, the leukocyte microvilli become extended and eventually form thin, 20 µm long tethers. Tether formation can be observed in blood vessels in vivo and in microfluidic flow chambers. Tethers can also be extracted using micropipette aspiration, biomembrane force probe, optical trap, or atomic force microscopy approaches. Here, we review the biomechanical properties of leukocyte tethers as gleaned from such measurements and discuss the advantages and disadvantages of each approach. We also review and discuss viscoelastic models that describe the dependence of tether formation on time, force, rate of loading, and cell activation. We close by emphasizing the need to combine experimental observations with quantitative models and computer simulations to understand how tether formation is affected by membrane tension, membrane reservoir, and interactions of the membrane with the cytoskeleton.
Collapse
|
|
39
|
Mylvaganam S, Riedl M, Vega A, Collins RF, Jaqaman K, Grinstein S, Freeman SA. Stabilization of Endothelial Receptor Arrays by a Polarized Spectrin Cytoskeleton Facilitates Rolling and Adhesion of Leukocytes. Cell Rep 2021; 31:107798. [PMID: 32579925 PMCID: PMC7548125 DOI: 10.1016/j.celrep.2020.107798] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 04/15/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022] Open
Abstract
Multivalent complexes of endothelial adhesion receptors (e.g., selectins) engage leukocytes to orchestrate their migration to inflamed tissues. Proper anchorage and sufficient density (clustering) of endothelial receptors are required for efficient leukocyte capture and rolling. We demonstrate that a polarized spectrin network dictates the stability of the endothelial cytoskeleton, which is attached to the apical membrane, at least in part, by the abundant transmembrane protein CD44. Single-particle tracking revealed that CD44 undergoes prolonged periods of immobilization as it tethers to the cytoskeleton. The CD44-spectrin "picket fence" alters the behavior of bystander molecules-notably, selectins-curtailing their mobility, inducing their apical accumulation, and favoring their clustering within caveolae. Accordingly, depletion of either spectrin or CD44 virtually eliminated leukocyte rolling and adhesion to the endothelium. Our results indicate that a unique spectrin-based apical cytoskeleton tethered to transmembrane pickets-notably, CD44-is essential for proper extravasation of leukocytes in response to inflammation.
Collapse
Affiliation(s)
- Sivakami Mylvaganam
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
| | - Magdalena Riedl
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada
| | - Anthony Vega
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Richard F Collins
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada
| | - Khuloud Jaqaman
- Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sergio Grinstein
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
| | - Spencer A Freeman
- Program in Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, 686 Bay Street, 19-9800, Toronto, ON M5G 0A4, Canada; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
| |
Collapse
|
|
40
|
Conran N, Embury SH. Sickle cell vaso-occlusion: The dialectic between red cells and white cells. Exp Biol Med (Maywood) 2021; 246:1458-1472. [PMID: 33794696 DOI: 10.1177/15353702211005392] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The pathophysiology of sickle cell anemia, a hereditary hemoglobinopathy, has fascinated clinicians and scientists alike since its description over 100 years ago. A single gene mutation in the HBB gene results in the production of abnormal hemoglobin (Hb) S, whose polymerization when deoxygenated alters the physiochemical properties of red blood cells, in turn triggering pan-cellular activation and pathological mechanisms that include hemolysis, vaso-occlusion, and ischemia-reperfusion to result in the varied and severe complications of the disease. Now widely regarded as an inflammatory disease, in recent years attention has included the role of leukocytes in vaso-occlusive processes in view of the part that these cells play in innate immune processes, their inherent ability to adhere to the endothelium when activated, and their sheer physical and potentially obstructive size. Here, we consider the role of sickle red blood cell populations in elucidating the importance of adhesion vis-a-vis polymerization in vaso-occlusion, review the direct adhesion of sickle red cells to the endothelium in vaso-occlusive processes, and discuss how red cell- and leukocyte-centered mechanisms are not mutually exclusive. Given the initial clinical success of crizanlizumab, a specific anti-P selectin therapy, we suggest that it is appropriate to take a holistic approach to understanding and exploring the complexity of vaso-occlusive mechanisms and the adhesive roles of the varied cell types, including endothelial cells, platelets, leukocytes, and red blood cells.
Collapse
Affiliation(s)
- Nicola Conran
- Hematology Center, University of Campinas-UNICAMP, Barão Geraldo 13083-8, Campinas, SP, Brazil
| | | |
Collapse
|
|
41
|
Zindel J, Peiseler M, Hossain M, Deppermann C, Lee WY, Haenni B, Zuber B, Deniset JF, Surewaard BGJ, Candinas D, Kubes P. Primordial GATA6 macrophages function as extravascular platelets in sterile injury. Science 2021; 371:371/6533/eabe0595. [PMID: 33674464 DOI: 10.1126/science.abe0595] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 01/08/2021] [Indexed: 12/14/2022]
Abstract
Most multicellular organisms have a major body cavity that harbors immune cells. In primordial species such as purple sea urchins, these cells perform phagocytic functions but are also crucial in repairing injuries. In mammals, the peritoneal cavity contains large numbers of resident GATA6+ macrophages, which may function similarly. However, it is unclear how cavity macrophages suspended in the fluid phase (peritoneal fluid) identify and migrate toward injuries. In this study, we used intravital microscopy to show that cavity macrophages in fluid rapidly form thrombus-like structures in response to injury by means of primordial scavenger receptor cysteine-rich domains. Aggregates of cavity macrophages physically sealed injuries and promoted rapid repair of focal lesions. In iatrogenic surgical situations, these cavity macrophages formed extensive aggregates that promoted the growth of intra-abdominal scar tissue known as peritoneal adhesions.
Collapse
Affiliation(s)
- J Zindel
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Visceral Surgery and Medicine, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - M Peiseler
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - M Hossain
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - C Deppermann
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - W Y Lee
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - B Haenni
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | - B Zuber
- Institute of Anatomy, University of Bern, Bern, Switzerland
| | - J F Deniset
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada
| | - B G J Surewaard
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada.,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - D Candinas
- Department of Visceral Surgery and Medicine, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - P Kubes
- Department of Pharmacology and Physiology, University of Calgary, Calgary, Alberta, Canada. .,Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| |
Collapse
|
|
42
|
Karki NR, Kutlar A. P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab. J Pain Res 2021; 14:849-856. [PMID: 33833562 PMCID: PMC8019662 DOI: 10.2147/jpr.s278285] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/13/2021] [Indexed: 01/01/2023] Open
Abstract
Microvascular vaso-occlusion driven pain crisis is the hallmark of sickle cell disease with profound morbidity and increased mortality. Selectins, most notably P-selectins have an integral role in this phenomenon. P-selection was first identified in 1989. In 2019, after 3 decades of basic, translational, and clinical work with this pathway, the US Food and Drug Administration approved a P-selectin antibody, crizanlizumab to reduce frequency of pain crisis in patients more than 16 years with sickle cell disease. We review the fundamentals of P-selectin pathobiology, P-selectin blocking agents, clinical data with the use of crizanlizumab and prospects of this novel class of drugs in the context of other treatments for painful vaso-occlusive episodes.
Collapse
Affiliation(s)
- Nabin Raj Karki
- Division of Hematology/Oncology, Augusta University, Augusta, GA, USA
| | - Abdullah Kutlar
- Division of Hematology/Oncology, Augusta University, Augusta, GA, USA
| |
Collapse
|
|
43
|
Coburn J, Garcia B, Hu LT, Jewett MW, Kraiczy P, Norris SJ, Skare J. Lyme Disease Pathogenesis. Curr Issues Mol Biol 2020; 42:473-518. [PMID: 33353871 DOI: 10.21775/cimb.042.473] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Lyme disease Borrelia are obligately parasitic, tick- transmitted, invasive, persistent bacterial pathogens that cause disease in humans and non-reservoir vertebrates primarily through the induction of inflammation. During transmission from the infected tick, the bacteria undergo significant changes in gene expression, resulting in adaptation to the mammalian environment. The organisms multiply and spread locally and induce inflammatory responses that, in humans, result in clinical signs and symptoms. Borrelia virulence involves a multiplicity of mechanisms for dissemination and colonization of multiple tissues and evasion of host immune responses. Most of the tissue damage, which is seen in non-reservoir hosts, appears to result from host inflammatory reactions, despite the low numbers of bacteria in affected sites. This host response to the Lyme disease Borrelia can cause neurologic, cardiovascular, arthritic, and dermatologic manifestations during the disseminated and persistent stages of infection. The mechanisms by which a paucity of organisms (in comparison to many other infectious diseases) can cause varied and in some cases profound inflammation and symptoms remains mysterious but are the subjects of diverse ongoing investigations. In this review, we provide an overview of virulence mechanisms and determinants for which roles have been demonstrated in vivo, primarily in mouse models of infection.
Collapse
Affiliation(s)
- Jenifer Coburn
- Center For Infectious Disease Research, Medical College of Wisconsin, 8701 Watertown Plank Rd., TBRC C3980, Milwaukee, WI 53226, USA
| | - Brandon Garcia
- Department of Microbiology and Immunology, East Carolina University, Brody School of Medicine, Greenville, NC 27858, USA
| | - Linden T Hu
- Department of Molecular Biology and Microbiology, Vice Dean of Research, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA
| | - Mollie W Jewett
- Immunity and Pathogenesis Division Head, Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 6900 Lake Nona Blvd. Orlando, FL 32827, USA
| | - Peter Kraiczy
- Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Goethe University Frankfurt, Paul-Ehrlich-Str. 40, 60596 Frankfurt, Germany
| | - Steven J Norris
- Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston, P.O. Box 20708, Houston, TX 77225, USA
| | - Jon Skare
- Professor and Associate Head, Texas A and M University, 8447 Riverside Pkwy, Bryan, TX 77807, USA
| |
Collapse
|
|
44
|
Lin J, Li X, Yin J, Qian J. Effect of Cyclic Stretch on Neuron Reorientation and Axon Outgrowth. Front Bioeng Biotechnol 2020; 8:597867. [PMID: 33425865 PMCID: PMC7793818 DOI: 10.3389/fbioe.2020.597867] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 11/23/2020] [Indexed: 01/30/2023] Open
Abstract
The directional alignment and outgrowth of neurons is a critical step of nerve regeneration and functional recovery of nerve systems, where neurons are exposed to a complex mechanical environment with subcellular structures such as stress fibers and focal adhesions acting as the key mechanical transducer. In this paper, we investigate the effects of cyclic stretch on neuron reorientation and axon outgrowth with a feasible stretching device that controls stretching amplitude and frequency. Statistical results indicate an evident frequency and amplitude dependence of neuron reorientation, that is, neurons tend to align away from stretch direction when stretching amplitude and frequency are large enough. On the other hand, axon elongation under cyclic stretch is very close to the reference case where neurons are not stretched. A mechanochemical framework is proposed by connecting the evolution of cellular configuration to the microscopic dynamics of subcellular structures, including stress fiber, focal adhesion, and microtubule, yielding theoretical predictions that are consistent with the experimental observations. The theoretical work provides an explanation of the neuron's mechanical response to cyclic stretch, suggesting that the contraction force generated by stress fiber plays an essential role in both neuron reorientation and axon elongation. This combined experimental and theoretical study on stretch-induced neuron reorientation may have potential applications in neurodevelopment and neuron regeneration.
Collapse
Affiliation(s)
- Ji Lin
- Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province, Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
| | - Xiaokeng Li
- State Key Laboratory of Fluid Power and Mechatronic Systems, Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province, School of Mechanical Engineering, Zhejiang University, Hangzhou, China
| | - Jun Yin
- State Key Laboratory of Fluid Power and Mechatronic Systems, Key Laboratory of 3D Printing Process and Equipment of Zhejiang Province, School of Mechanical Engineering, Zhejiang University, Hangzhou, China
| | - Jin Qian
- Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province, Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
| |
Collapse
|
|
45
|
Kilb MF, Engemann VI, Siddique A, Stark RW, Schmitz K. Immobilisation of CXCL8 gradients in microfluidic devices for migration experiments. Colloids Surf B Biointerfaces 2020; 198:111498. [PMID: 33302150 DOI: 10.1016/j.colsurfb.2020.111498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/23/2020] [Accepted: 11/27/2020] [Indexed: 11/29/2022]
Abstract
The release of inflammatory chemokines leads to the formation of chemokine gradients that result in the directed migration of immune cells to the site of injury. In this process, cells respond to soluble gradients (chemotaxis) as well as to immobilised gradients (haptotaxis). Surface-bound chemokine gradients are mostly presented by endothelial cells and supported by glycosaminoglycans (GAGs), such as heparan sulfate, involving the GAG binding site of chemokines. Microfluidic devices have been used to analyse cell migration along soluble chemokine gradients, as these devices allow the generation of stable gradients with resolutions in the range of microns. To immobilise well-controlled soluble gradients of interleukin-8 (CXCL8), an inflammatory chemokine, we developed a simple procedure using a heparin-coated PDMS-microfluidic device. We used these immobilised gradients for migration experiments with CXCL8-responsive THP-1 cells and confirmed directed cell migration. This setup might be useful for the examination of factors that may alter chemotaxis and haptotaxis as well as synergistic and antagonistic effects of other soluble and immobilised chemokines.
Collapse
Affiliation(s)
- Michelle F Kilb
- Technical University of Darmstadt, Clemens-Schöpf-Institute of Organic Chemistry and Biochemistry, Alarich-Weiss-Straße 8, 64287, Darmstadt, Germany
| | - Victoria I Engemann
- Technical University of Darmstadt, Clemens-Schöpf-Institute of Organic Chemistry and Biochemistry, Alarich-Weiss-Straße 8, 64287, Darmstadt, Germany
| | - Asma Siddique
- Technical University of Darmstadt, Institute of Materials Science, Physics of Surfaces, Alarich-Weiss-Straße 16, 64287. Darmstadt, Germany
| | - Robert W Stark
- Technical University of Darmstadt, Institute of Materials Science, Physics of Surfaces, Alarich-Weiss-Straße 16, 64287. Darmstadt, Germany
| | - Katja Schmitz
- Technical University of Darmstadt, Clemens-Schöpf-Institute of Organic Chemistry and Biochemistry, Alarich-Weiss-Straße 8, 64287, Darmstadt, Germany.
| |
Collapse
|
|
46
|
Ilyas S, Sher M, Du E, Asghar W. Smartphone-based sickle cell disease detection and monitoring for point-of-care settings. Biosens Bioelectron 2020; 165:112417. [PMID: 32729535 PMCID: PMC7484220 DOI: 10.1016/j.bios.2020.112417] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/24/2020] [Accepted: 06/29/2020] [Indexed: 12/20/2022]
Abstract
Sickle cell disease (SCD) is a worldwide hematological disorder causing painful episodes, anemia, organ damage, stroke, and even deaths. It is more common in sub-Saharan Africa and other resource-limited countries. Conventional laboratory-based diagnostic methods for SCD are time-consuming, complex, and cannot be performed at point-of-care (POC) and home settings. Optical microscope-based classification and counting demands a significant amount of time, extensive setup, and cost along with the skilled human labor to distinguish the normal red blood cells (RBCs) from sickled cells. There is an unmet need to develop a POC and home-based test to diagnose and monitor SCD and reduce mortality in resource-limited settings. An early-stage and timely diagnosis of SCD can help in the effective management of the disease. In this article, we utilized a smartphone-based image acquisition method for capturing RBC images from the SCD patients in normoxia and hypoxia conditions. A computer algorithm is developed to differentiate RBCs from the patient's blood before and after cell sickling. Using the developed smartphone-based technique, we obtained similar percentage of sickle cells in blood samples as analyzed by conventional method (standard microscope). The developed method of testing demonstrates the potential utility of the smartphone-based test for reducing the overall cost of screening and management for SCD, thus increasing the practicality of smartphone-based screening technique for SCD in low-resource settings. Our setup does not require any special storage requirements. This is the characteristic advantage of our technique as compared to other hemoglobin-based POC diagnostic techniques.
Collapse
Affiliation(s)
- Shazia Ilyas
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, 33431, USA; Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL, 33431, USA
| | - Mazhar Sher
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, 33431, USA; Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL, 33431, USA
| | - E Du
- Department of Ocean and Mechanical Engineering, Florida Atlantic University, Boca Raton, FL, 33431, USA; Department of Biological Sciences (Courtesy Appointment), Florida Atlantic University, Boca Raton, FL, 33431, USA
| | - Waseem Asghar
- Department of Computer & Electrical Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, 33431, USA; Asghar-Lab, Micro and Nanotechnology in Medicine, College of Engineering and Computer Science, Boca Raton, FL, 33431, USA; Department of Biological Sciences (Courtesy Appointment), Florida Atlantic University, Boca Raton, FL, 33431, USA.
| |
Collapse
|
|
47
|
Spirina NN, Spirin NN, Dubchenco EA, Boyko AN. [Effect of different groups of first line DMT on endothelial damage in multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova 2020; 120:83-88. [PMID: 32844636 DOI: 10.17116/jnevro202012007283] [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: 11/17/2022]
Abstract
INTRODUCTION Vascular changes, including destabilization of the blood-brain barrier, are common pathological signs in multiple sclerosis (MS). There are prerequisites, which indicate the direct effects of disease modifying therapy (DMT) on the state of the vascular wall and reduce the damage to the endothelium in MS. AIM OF THIS STUDY Was to identify and evaluate the relationship of endothelial dysfunction in patients with multiple sclerosis with used DMT. MATERIALS AND METHODS The study included 85 patients with a reliable diagnosis of MS according to the McDonald criteria of 2010 (56 women, 29 men) aged from 17 to 62 years (average age 36.3±1.2 years). All patients underwent a comprehensive clinical and neurological examination, laboratory tests (blood serum analysis for the content of adhesion molecules sICAM-1, sPECAM-1, sE-selectin, sP-selectin, for the content of homocysteine and matrix metalloproteinase 9 (MMR-9) by ELISA; blood plasma analysis for Von Willebrand factor antigen (vWf) by ELISA). The results of the study indicate a decrease of endothelial damage in MS during interferon therapy. Its also allow the use of indicators such as von Willebrand factor antigen, sPECAM-1, sE-selectin levels as potential markers of the effectiveness of DMT.
Collapse
Affiliation(s)
- N N Spirina
- Yaroslavl State Medical University, Yaroslavl, Russia
| | - N N Spirin
- Yaroslavl State Medical University, Yaroslavl, Russia
| | - E A Dubchenco
- Federal Center of Brain and Neurotechnologies, Mocsow, Russia
| | - A N Boyko
- Federal Center of Brain and Neurotechnologies, Mocsow, Russia.,Pirogov Russian National Research University, Moscow, Russia
| |
Collapse
|
|
48
|
Karimi F, Thombare VJ, Hutton CA, O'Connor AJ, Qiao GG, Heath DE. Biomaterials functionalized with nanoclusters of integrin- and syndecan-binding ligands improve cell adhesion and mechanosensing under shear flow conditions. J Biomed Mater Res A 2020; 109:313-325. [PMID: 32490581 DOI: 10.1002/jbm.a.37024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 04/20/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022]
Abstract
We have engineered biomaterials that display nanoclusters of ligands that bind both integrin and syndecan-4 cell receptors. These surfaces regulate cell behaviors under static conditions including adhesion, spreading, actin stress fiber formation, and migration. The syndecan-4 receptors are also critical mediators of cellular mechanotransduction. In this contribution we assess whether this novel class of materials can regulate the response of cells to applied mechanical stimulation, using the shear stress imparted by laminar fluid flow as a model stimulus. Specifically, we assess endothelial cell detachment due to flow, cell alignment due to flow, and cell adhesion from the flowing fluid. A high degree of cell retention was observed on surfaces containing integrin-binding ligands or a mixed population of integrin- and syndecan-binding ligands. However, the presence of both ligand types was necessary for the cells to align in the direction of flow. These results imply that integrin engagement is necessary for adhesion strength, but engagement of both receptor types aids in appropriate mechanotransduction. Additionally, it was found that surfaces functionalized with both ligand types were able to scavenge a larger number of cells from flow, and to do so at a faster rate, compared to surfaces functionalized with only integrin- or syndecan-binding ligands. These results show that interfaces functionalized with both integrin- and syndecan-binding ligands regulate a significant range of biophysical cell behaviors in response to shear stress.
Collapse
Affiliation(s)
- Fatemeh Karimi
- Department of Biomedical Engineering, Particulate Fluids Processing Centre, University of Melbourne, Parkville, Victoria, Australia.,Polymer Science Group, Department of Chemical Engineering, Particulate Fluid Processing Centre, University of Melbourne, Parkville, Victoria, Australia.,Graduate School of Biomedical Engineering, University of New South Wales, Sydney, Australia
| | - Varsha Jagannath Thombare
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia
| | - Craig A Hutton
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria, Australia
| | - Andrea J O'Connor
- Department of Biomedical Engineering, Particulate Fluids Processing Centre, University of Melbourne, Parkville, Victoria, Australia
| | - Greg G Qiao
- Polymer Science Group, Department of Chemical Engineering, Particulate Fluid Processing Centre, University of Melbourne, Parkville, Victoria, Australia
| | - Daniel E Heath
- Department of Biomedical Engineering, Particulate Fluids Processing Centre, University of Melbourne, Parkville, Victoria, Australia
| |
Collapse
|
|
49
|
Marchetti L, Engelhardt B. Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation. VASCULAR BIOLOGY 2020; 2:H1-H18. [PMID: 32923970 PMCID: PMC7439848 DOI: 10.1530/vb-19-0033] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 03/20/2020] [Indexed: 12/18/2022]
Abstract
To maintain the homeostatic environment required for proper function of CNS neurons the endothelial cells of CNS microvessels tightly regulate the movement of ions and molecules between the blood and the CNS. The unique properties of these blood vascular endothelial cells are termed blood-brain barrier (BBB) and extend to regulating immune cell trafficking into the immune privileged CNS during health and disease. In general, extravasation of circulating immune cells is a multi-step process regulated by the sequential interaction of adhesion and signalling molecules between the endothelial cells and the immune cells. Accounting for the unique barrier properties of CNS microvessels, immune cell migration across the BBB is distinct and characterized by several adaptations. Here we describe the mechanisms that regulate immune cell trafficking across the BBB during immune surveillance and neuroinflammation, with a focus on the current state-of-the-art in vitro and in vivo imaging observations.
Collapse
Affiliation(s)
- Luca Marchetti
- Theodor Kocher Institute, University of Bern, Bern, Switzerland
| | | |
Collapse
|
|
50
|
Man Y, Goreke U, Kucukal E, Hill A, An R, Liu S, Bode A, Solis-Fuentes A, Nayak LV, Little JA, Gurkan UA. Leukocyte adhesion to P-selectin and the inhibitory role of Crizanlizumab in sickle cell disease: A standardized microfluidic assessment. Blood Cells Mol Dis 2020; 83:102424. [PMID: 32208292 DOI: 10.1016/j.bcmd.2020.102424] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/08/2020] [Indexed: 01/21/2023]
Abstract
Upregulated expression of P-selectin on activated endothelium and platelets significantly contributes to the initiation and progression of vaso-occlusive crises (VOC), a major cause of morbidity in sickle cell disease (SCD). Crizanlizumab (ADAKVEO®), a humanized monoclonal antibody against P-selectin, primarily inhibits the interaction between leukocytes and P-selectin, and has been shown to decrease the frequency of VOCs in clinical trials. However, the lack of reliable in vitro assays that objectively measure leukocyte adhesion to P-selectin remains a critical barrier to evaluating and improving the therapeutic treatment in SCD. Here, we present a standardized microfluidic BioChip whole blood adhesion assay to assess leukocyte adhesion to P-selectin under physiologic flow conditions. Our results demonstrated heterogeneous adhesion by leukocytes to immobilized P-selectin, and dose-dependent inhibition of this adhesion following pre-exposure to Crizanlizumab. Importantly, treatment with Crizanlizumab following adhesion to P-selectin promoted detachment of rolling, but not of firmly adherent leukocytes. Taken together, our results suggest that the microfluidic BioChip system is a promising in vitro assay with which to screen patients, monitor treatment response, and guide current and emerging anti-adhesive therapies in SCD.
Collapse
Affiliation(s)
- Yuncheng Man
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Utku Goreke
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Erdem Kucukal
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ailis Hill
- Department of Hematology and Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ran An
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Shichen Liu
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Allison Bode
- Department of Hematology and Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ambar Solis-Fuentes
- Department of Hematology and Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lalitha V Nayak
- Department of Hematology and Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jane A Little
- Department of Hematology and Oncology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Umut A Gurkan
- Department of Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
| |
Collapse
|