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Molecular Mechanisms Involved in Lymphocyte Recruitment in Inflamed Brain Microvessels: Critical Roles for P-Selectin Glycoprotein Ligand-1 and Heterotrimeric Gi-Linked Receptors
Open accessAbstract
Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice. No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation. When brain venules were activated by pretreating mice with TNF-α or LPS, proteolipid protein 139–151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules. E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis. LFA-1/ICAM-1 and α4 integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity. Firm arrest was mainly mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for Gi protein-dependent signaling in vessels from nonlymphoid districts. In conclusion, our data unveils the molecular mechanisms controlling the recruitment of autoreactive lymphocytes in inflamed cerebral vessels and suggest new insights into the pathogenesis of autoimmune inflammatory diseases of the CNS.
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“This results in T cell rolling and eventual arrest mediated by LFA-1-ICAM-1 and VLA-4-VCAM-1 interactions (Fig. 4), as observed by using the proteolipid protein (PLP139-151) immunization model of EAE (110).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [110]
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“Similar to steady state, the process of diapedesis during CNS autoimmune disease involves T cell interactions with endothelial selectins through P-selectin glycoprotein ligand–1 (PSGL-1), although the requirement for selectins is not absolute.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [110]
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“In addition to adhesion molecules, T cell arrest is often linked to G protein signaling in vessels (110), which is facilitated by chemokines such as CCL19 and CCL21 that are produced by vascular endothelial cells (113).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [110]
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Metadata
- Authors
- Piccio, L., Rossi, B., Scarpini, E., Laudanna, C., Giagulli, C., Issekutz, A. C., Vestweber, D., Butcher, E. C., & Constantin, G.
- Affiliations
- University of Verona (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Dalhousie University (CA)
- University of Münster (DE)
- Stanford University (US)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-02
- Volume
- 168
- Issue
- 4
- Pages
- 1940-1949
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1960336193
- Cited by
- 245
- References
- 56
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 7 · 2016: 7 · 2015: 12 · 2014: 11 · 2013: 8 · 2012: 16
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Fondazione Italiana Sclerosi Multipla
- Deutsche Forschungsgemeinschaft
- Consiglio Nazionale delle Ricerche
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- lymphocyte recruitment, PSGL-1, E-selectin, P-selectin, endothelial activation, multiple sclerosis, experimental autoimmune encephalomyelitis, autoreactive T cells, heterotrimeric G protein signaling, pertussis toxin, intravital microscopy, TNF-α, LPS, lymphocyte-endothelial interactions
- MeSH terms
- Animals, Autoantigens, Brain, Cell Movement, Cerebrovascular Circulation, Encephalomyelitis, Autoimmune, Experimental, Endothelium, Vascular, Female, Hemodynamics, Membrane Glycoproteins, Microcirculation, Microscopy, Fluorescence, Receptors, Cell Surface, T-Lymphocytes, Venules, Cell Adhesion Molecules, Integrins, Models, Immunological, Selectins, GTP-Binding Protein alpha Subunits, Gi-Go, Mice
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