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CD44 Deficiency Contributes To Enhanced Experimental Autoimmune Encephalomyelitis: A Role In Immune Cells And Vascular Cells Of The Blood-brain Barrier.

K. Flynn, M. Michaud, J. Madri
Published 2013 · Biology, Medicine

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Adhesion molecule CD44 is expressed by multiple cell types and is implicated in various cellular and immunological processes. In this study, we examined the effect of global CD44 deficiency on myelin oligodendrocyte glycoprotein peptide (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Compared to C57BL/6 wild-type mice, CD44-deficient mice presented with greater disease severity, increased immune cell numbers in the central nervous system, and increased anti-MOG antibody and proinflammatory cytokine production, especially those associated with T helper 17 (Th17) cells. Further, decreased numbers of peripheral CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) were observed in CD44-knockout mice throughout the disease course. CD44-knockout CD4 T cells exhibited reduced transforming growth factor-β receptor type I (TGF-β RI) expression that did not impart a defect in Treg polarization in vitro, but did correlate with enhanced Th17 polarization in vitro. Further, EAE in bone marrow-chimeric animals suggested CD44 expression on both circulating and noncirculating cells limited disease severity. Endothelial expression of CD44 limited T-cell adhesion to and transmigration through murine endothelial monolayers in vitro. Importantly, we also identified increased permeability of the blood-brain barrier in vivo in CD44-deficient mice before and following immunization. These data suggest that CD44 has multiple protective roles in EAE, with effects on cytokine production, T-cell differentiation, T-cell-endothelial cell interactions, and blood-brain barrier integrity.
This paper references
10.1038/nrm1004
CD44: From adhesion molecules to signalling regulators
H. Ponta (2003)
10.4049/jimmunol.171.1.462
Rat and Human Myelin Oligodendrocyte Glycoproteins Induce Experimental Autoimmune Encephalomyelitis by Different Mechanisms in C57BL/6 Mice1
A. R. Oliver (2003)
10.1073/pnas.0407378102
RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: A different interpretation of redundancy
S. Nedvetzki (2004)
10.1101/GAD.11.8.996
Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation.
G. Kaya (1997)
10.4049/jimmunol.180.4.2625
CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response1
P. Huebener (2008)
10.1038/nm0695-558
Anti-CD44 treatment abrogates tissue aedema and leukocyte infiltration in murine arthrtis
K. Mikecz (1995)
Platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) tyrosine phosphorylation state changes during vasculogenesis in the murine conceptus.
E. Pinter (1997)
10.1191/1352458503ms965oa
Blood-brain barrier disruption in multiple sclerosis
A. Minagar (2003)
10.4049/jimmunol.1002681
4-1BB Triggering Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Balance between Th17 and Regulatory T Cells
Y. H. Kim (2011)
The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the pathogenesis of experimental autoimmune encephalomyelitis.
D. Graesser (1998)
10.1016/J.JNEUROIM.2007.11.016
Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease
R. O'connor (2008)
10.1016/j.phrs.2008.02.001
TGF-beta1 targets the GSK-3beta/beta-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts.
F. Caraci (2008)
10.1128/IAI.00949-09
CD44 Deficiency Is Associated with Enhanced Escherichia coli-Induced Proinflammatory Cytokine and Chemokine Release by Peritoneal Macrophages
G. J. W. van der Windt (2009)
10.1155/2000/79045
Cell Migration in the Immune System: the Evolving Inter-Related Roles of Adhesion Molecules and Proteinases
J. Madri (2000)
10.2174/092986708784221458
Role of the innate immune system in autoimmune inflammatory demyelination.
K. O'brien (2008)
10.1084/jem.20030152
Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3
W. Chen (2003)
10.1038/nm1651
Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation
H. Kébir (2007)
10.4049/jimmunol.1003511
Glycogen Synthase Kinase-3 Is an Early Determinant in the Differentiation of Pathogenic Th17 Cells
E. Beurel (2011)
10.1074/jbc.M204320200
Hyaluronan Promotes Signaling Interaction between CD44 and the Transforming Growth Factor β Receptor I in Metastatic Breast Tumor Cells*
L. Bourguignon (2002)
10.1038/nature04753
Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells
E. Bettelli (2006)
10.1097/00005072-199111000-00009
Localization of the CD44 Glycoprotein to Fibrous Astrocytes in Normal White Matter and to Reactive Astrocytes in Active Lesions in Multiple Sclerosis
N. Girgrah (1991)
10.1038/ni.1716
C-C chemokine receptor 6–regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE
Andrea Reboldi (2009)
10.1038/ni1221
Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3
M. Martin (2005)
10.1038/nature06878
TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function
L. Zhou (2008)
10.1038/nm1279
Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation
S. A. Back (2005)
10.1074/jbc.C109.078238
Smad3 Differentially Regulates the Induction of Regulatory and Inflammatory T Cell Differentiation*
Gustavo J Martinez (2009)
10.1128/IAI.73.1.50-61.2005
Role of CD44 and Its v7 Isoform in Staphylococcal Enterotoxin B-Induced Toxic Shock: CD44 Deficiency on Hepatic Mononuclear Cells Leads to Reduced Activation-Induced Apoptosis That Results in Increased Liver Damage
R. Mckallip (2005)
10.1038/nprot.2006.327
Isolation of murine microglial cells for RNA analysis or flow cytometry
A. E. Cardona (2006)
10.1038/nrn1824
Astrocyte–endothelial interactions at the blood–brain barrier
N. Abbott (2006)
10.1164/RCCM.200608-1243OC
Galectin-9 Inhibits CD44–Hyaluronan Interaction and Suppresses a Murine Model of Allergic Asthma
S. Katoh (2007)
10.1016/S0945-053X(01)00186-X
CD44-mediated uptake and degradation of hyaluronan.
W. Knudson (2002)
10.1016/S0945-053X(01)00184-6
Hyaluronan and its catabolic products in tissue injury and repair.
P. Noble (2002)
10.1016/j.jneuroim.2010.08.011
Blood–brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE
J. Bennett (2010)
10.1038/cr.2008.327
Phospho-control of TGF-β superfamily signaling
Katharine H. Wrighton (2009)
10.1096/fj.09-141978
Cellular mechanisms of IL‐17‐induced blood‐brain barrier disruption
Jula Huppert (2010)
10.1002/(SICI)1097-0215(19990129)80:3<387::AID-IJC9>3.0.CO;2-T
Involvement of CD44 in matrix metalloproteinase‐2 regulation in human melanoma cells
K. Takahashi (1999)
10.4049/jimmunol.178.4.2469
CD44 Is a Negative Regulator of Acute Pulmonary Inflammation and Lipopolysaccharide-TLR Signaling in Mouse Macrophages1
J. Liang (2007)
10.1038/nri2550
Autoimmune T cell responses in the central nervous system
J. Goverman (2009)
10.1126/SCIENCE.1069659
Resolution of Lung Inflammation by CD44
P. Teder (2002)
10.1016/j.molimm.2009.08.026
Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS.
J. Muto (2009)
10.1016/S0002-9440(10)64498-7
CD44 deficiency leads to enhanced neutrophil migration and lung injury in Escherichia coli pneumonia in mice.
Q. Wang (2002)
Transforming growth factor-beta induces development of the T(H)17 lineage.
P. R. Mangan (2006)
10.1084/JEM.183.6.2593
T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines
F. Fossiez (1996)
10.1242/jcs.00954
The role of the CD44 transmembrane and cytoplasmic domains in co-ordinating adhesive and signalling events
R. Thorne (2004)
10.4049/jimmunol.175.5.3025
Natural Recovery and Protection from Autoimmune Encephalomyelitis: Contribution of CD4+CD25+ Regulatory Cells within the Central Nervous System1
Mandy J McGeachy (2005)
10.1006/JAUT.1999.0294
CD44 involvement in experimental collagen-induced arthritis (CIA).
S. Nedvetzki (1999)
10.4049/jimmunol.0900191
CD44 Costimulation Promotes FoxP3+ Regulatory T Cell Persistence and Function via Production of IL-2, IL-10, and TGF-β1
P. Bollyky (2009)
10.1016/j.immuni.2009.04.010
Mechanisms of foxp3+ T regulatory cell-mediated suppression.
E. Shevach (2009)
Toll-like receptormediated cytokine production is differentially regulated by glycogen synthase kinase
M Martin (2005)
10.1126/SCIENCE.278.5338.672
Requirement for CD44 in activated T cell extravasation into an inflammatory site.
H. Degrendele (1997)
10.1101/GAD.14.2.163
Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis.
Q. Yu (2000)
10.1016/j.coph.2009.04.008
Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity.
Shomyseh Sanjabi (2009)
Th17 Cells in MS and Experimental Autoimmune Encephalomyelitis.
H. Hofstetter (2009)
10.1007/s00424-007-0212-8
The endothelial glycocalyx: composition, functions, and visualization
S. Reitsma (2007)
Phospho - control of TGF - beta superfamily signaling
KH Wrighton (2009)
10.1096/fj.04-2445com
MMP‐2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP‐9 expression and activity
J. Esparza (2004)
10.1189/jlb.69.6.860
Novel chemokine functions in lymphocyte migration through vascular endothelium under shear flow
G. Cinamon (2001)
10.1002/ana.20913
How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis
L. Steinman (2006)
10.1101/gad.1590908
Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling.
X. Guo (2008)
10.1016/j.cell.2008.07.025
TGF-β: A Master of All T Cell Trades
M. Li (2008)
10.1074/JBC.275.20.14939
Hyaluronan Anchoring and Regulation on the Surface of Vascular Endothelial Cells Is Mediated through the Functionally Active Form of CD44*
A. Nandi (2000)
10.1172/JCI13595
Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice.
D. Graesser (2002)
10.1073/PNAS.96.12.6896
Antibodies to CD44 and integrin alpha4, but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment.
S. Brocke (1999)
10.1182/blood-2008-04-150383
CD44-specific antibody treatment and CD44 deficiency exert distinct effects on leukocyte recruitment in experimental arthritis.
Gábor Hutás (2008)
10.1182/BLOOD-2005-06-2277
Suppressor activity and potency among regulatory T cells is discriminated by functionally active CD44.
M. Firan (2006)
This information is current as Fibrotic Response Healing by Regulating the Inflammatory and CD 44 Is Critically Involved in Infarct
P. Huebener (2008)
10.1093/INTIMM/DXH029
IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells.
X. Zhang (2004)
CD 44 involvement in experimental collageninduced arthritis ( CIA )
S Nedvetzki (1999)
10.1007/978-1-61779-185-7_24
MMP-mediated disruption of claudin-5 in the blood-brain barrier of rat brain after cerebral ischemia.
Y. Yang (2011)
10.1159/000082072
Natural versus adaptive regulatory T cells.
L. Cassis (2005)
10.4049/jimmunol.1004043
CD44 Reciprocally Regulates the Differentiation of Encephalitogenic Th1/Th17 and Th2/Regulatory T Cells through Epigenetic Modulation Involving DNA Methylation of Cytokine Gene Promoters, Thereby Controlling the Development of Experimental Autoimmune Encephalomyelitis
H. Guan (2011)
10.1097/01.WOX.0000301299.30646.e6
Galectin-9 inhibits CD44-hyaluronan interaction and suppresses a mirine model of allergic asthma
S. Katoh (2007)
10.1088/1478-3975/6/2/025014
Viscoelastic response of a model endothelial glycocalyx.
N. Nijenhuis (2009)
Axin and GSK 3control Smad 3 protein stability and modulate TGFsignaling
X Guo (2008)
10.1073/PNAS.97.1.285
Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody.
L. Weiss (2000)



This paper is referenced by
10.1016/j.jad.2015.12.069
The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability.
F. Ventorp (2016)
10.1007/s12031-016-0835-3
CD44 Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like Behavior in Mice
R. Barzilay (2016)
10.1016/j.cellimm.2020.104242
Sex differences in EAE reveal common and distinct cellular and molecular components.
Jack T Wiedrick (2020)
10.1161/ATVBAHA.117.309385
CD44 Promotes Inflammation and Extracellular Matrix Production During Arteriovenous Fistula Maturation
G. Kuwahara (2017)
10.1007/s10456-013-9346-9
CD44 regulates vascular endothelial barrier integrity via a PECAM-1 dependent mechanism
K. Flynn (2013)
10.5692/clinicalneurol.cn-000582
[A case of multiple sclerosis with bilateral intermediate uveitis].
Hiroto Nakano (2015)
10.1073/pnas.1525086113
Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization
H. Kuipers (2016)
10.3389/fncel.2015.00175
CD44: molecular interactions, signaling and functions in the nervous system
J. Dzwonek (2015)
10.3389/fimmu.2017.00321
Role of Anti-Osteopontin Antibodies in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
N. Clemente (2017)
10.1093/cvr/cvy167
A disintegrin and metalloproteinase 15-mediated glycocalyx shedding contributes to vascular leakage during inflammation
Xiaoyuan Yang (2018)
10.1074/jbc.M113.529313
CD44 Regulation of Endothelial Cell Proliferation and Apoptosis via Modulation of CD31 and VE-cadherin Expression*
M. Tsuneki (2014)
10.1016/j.isci.2018.12.020
Quantitative Proteomics Reveals the Dynamic Protein Landscape during Initiation of Human Th17 Cell Polarization
Subhash Tripathi (2019)
10.21037/sci.2020.02.02
CD44 expression in stem cells and niche microglia/macrophages following ischemic stroke.
Rikako Sawada (2020)
10.1016/j.matbio.2018.03.022
Hyaluronan in immune dysregulation and autoimmune diseases.
N. Nagy (2019)
10.1007/s12035-020-02004-2
Conventional Treatment of Glioblastoma Reveals Persistent CD44+ Subpopulations
Johann Mar Gudbergsson (2020)
10.1016/j.neuroscience.2013.10.050
White matter astrocytes in health and disease
I. Lundgaard (2014)
10.1002/cbin.10710
Adoptive transfer of T regulatory cells inhibits lipopolysaccharide‐induced inflammation in fetal brain tissue in a late‐pregnancy preterm birth mouse model
Fan Wang (2017)
10.1002/glia.23104
Identification of highly connected hub genes in the protective response program of human macrophages and microglia activated by alpha B‐crystallin
I. Holtman (2017)
10.1016/j.brainres.2020.146950
CD44 expression in the cuprizone model
Christin Reinbach (2020)
10.1016/j.pnpbp.2018.12.019
Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk
A. Wang (2019)
10.3126/jcmsn.v14i3.19381
Increase in MMP-9 Expressing CD11b+ cells in a CD44 Dependent Way Reduces Severity of Experimental Autoimmune Encephalomyelitis
Sujata Kar (2018)
10.4049/jimmunol.1501171
CD43 Functions as an E-Selectin Ligand for Th17 Cells In Vitro and Is Required for Rolling on the Vascular Endothelium and Th17 Cell Recruitment during Inflammation In Vivo
F. Velázquez (2016)
This information is current as In Vivo Th 17 Cell Recruitment during Inflammation Rolling on the Vascular Endothelium and Th 17 Cells In Vitro and Is Required for CD 43 Functions as an E-Selectin Ligand for Alcaide
F. Velázquez (2015)
10.1177/0271678X18767748
Hyaluronan impairs the barrier integrity of brain microvascular endothelial cells through a CD44-dependent pathway
Abraham Al-Ahmad (2018)
10.1128/MCB.00671-14
Adhesion Molecule-Mediated Hippo Pathway Modulates Hemangioendothelioma Cell Behavior
M. Tsuneki (2014)
10.1007/s00213-015-3914-1
Multivariate analysis of subjective responses to d-amphetamine in healthy volunteers finds novel genetic pathway associations
H. Yarosh (2015)
10.1038/labinvest.2015.61
A hydrogel-endothelial cell implant mimics infantile hemangioma: modulation by survivin and the Hippo pathway
M. Tsuneki (2015)
10.1016/j.autrev.2015.06.006
Selectin-mediated leukocyte trafficking during the development of autoimmune disease.
Stefano Angiari (2015)
10.1042/CS20140714
PECAM-1 isoforms, eNOS and endoglin axis in regulation of angiogenesis.
S. Park (2015)
10.1002/JLB.3A0918-345RR
Cxcl17−/− mice develop exacerbated disease in a T cell‐dependent autoimmune model
M. Hernández-Ruiz (2019)
10.3390/ijms21175988
Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System
Alec Peters (2020)
10.1007/s12035-015-9131-4
Korean Red Ginseng and Ginsenoside-Rb1/-Rg1 Alleviate Experimental Autoimmune Encephalomyelitis by Suppressing Th1 and Th17 Cells and Upregulating Regulatory T Cells
M. Lee (2015)
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