RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis
T-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokin...
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doaj-026acbef7ed748a7bfaf311f9ba1ee892020-11-25T02:24:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-05-01910.3389/fimmu.2018.01235333447RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple SclerosisAlba Manresa-Arraut0Flemming Fryd Johansen1Cord Brakebusch2Shohreh Issazadeh-Navikas3Henrik Hasseldam4Neuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNeuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCytoskeletal Organization Group, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNeuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkNeuroinflammation Unit, Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkT-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokine production, integrin expression, and migration. These processes are crucial for the T-cells’ ability to mediate inflammatory processes in autoimmune diseases such as MS. RhoA is a ubiquitously expressed small GTPase well described as a regulator of the actin cytoskeleton. It is essential for embryonic development and together with other Rho GTPases controls various cellular processes such as cell development, shaping, proliferation, and locomotion. However, the specific contribution of RhoA to these processes in T-cells in general, and in autoreactive T-cells in particular, has not been fully characterized. Using mice with a T-cell specific deletion of the RhoA gene (RhoAfl/flLckCre+), we investigated the role of RhoA in T-cell development, functionality, and encephalitogenic potential in EAE. We show that lack of RhoA specifically in T-cells results in reduced numbers of mature T-cells in thymus and spleen but normal counts in peripheral blood. EAE induction in RhoAfl/flLckCre+ mice results in significantly reduced disease incidence and severity, which coincides with a reduced CNS T-cell infiltration. Besides presenting reduced migratory capacity, both naïve and autoreactive effector T-cells from RhoAfl/flLckCre+ mice show decreased viability, proliferative capacity, and an activation profile associated with reduced production of Th1 pro-inflammatory cytokines. Our study demonstrates that RhoA is a central regulator of several archetypical T-cell responses, and furthermore points toward RhoA as a new potential therapeutic target in diseases such as MS, where T-cell activity plays a central role.https://www.frontiersin.org/article/10.3389/fimmu.2018.01235/fullRhoAmultiple sclerosisexperimental autoimmune encephalomyelitisT-cellneuroinflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alba Manresa-Arraut Flemming Fryd Johansen Cord Brakebusch Shohreh Issazadeh-Navikas Henrik Hasseldam |
spellingShingle |
Alba Manresa-Arraut Flemming Fryd Johansen Cord Brakebusch Shohreh Issazadeh-Navikas Henrik Hasseldam RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis Frontiers in Immunology RhoA multiple sclerosis experimental autoimmune encephalomyelitis T-cell neuroinflammation |
author_facet |
Alba Manresa-Arraut Flemming Fryd Johansen Cord Brakebusch Shohreh Issazadeh-Navikas Henrik Hasseldam |
author_sort |
Alba Manresa-Arraut |
title |
RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis |
title_short |
RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis |
title_full |
RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis |
title_fullStr |
RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis |
title_full_unstemmed |
RhoA Drives T-Cell Activation and Encephalitogenic Potential in an Animal Model of Multiple Sclerosis |
title_sort |
rhoa drives t-cell activation and encephalitogenic potential in an animal model of multiple sclerosis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-05-01 |
description |
T-cells are known to be intimately involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). T-cell activation is controlled by a range of intracellular signaling pathways regulating cellular responses such as proliferation, cytokine production, integrin expression, and migration. These processes are crucial for the T-cells’ ability to mediate inflammatory processes in autoimmune diseases such as MS. RhoA is a ubiquitously expressed small GTPase well described as a regulator of the actin cytoskeleton. It is essential for embryonic development and together with other Rho GTPases controls various cellular processes such as cell development, shaping, proliferation, and locomotion. However, the specific contribution of RhoA to these processes in T-cells in general, and in autoreactive T-cells in particular, has not been fully characterized. Using mice with a T-cell specific deletion of the RhoA gene (RhoAfl/flLckCre+), we investigated the role of RhoA in T-cell development, functionality, and encephalitogenic potential in EAE. We show that lack of RhoA specifically in T-cells results in reduced numbers of mature T-cells in thymus and spleen but normal counts in peripheral blood. EAE induction in RhoAfl/flLckCre+ mice results in significantly reduced disease incidence and severity, which coincides with a reduced CNS T-cell infiltration. Besides presenting reduced migratory capacity, both naïve and autoreactive effector T-cells from RhoAfl/flLckCre+ mice show decreased viability, proliferative capacity, and an activation profile associated with reduced production of Th1 pro-inflammatory cytokines. Our study demonstrates that RhoA is a central regulator of several archetypical T-cell responses, and furthermore points toward RhoA as a new potential therapeutic target in diseases such as MS, where T-cell activity plays a central role. |
topic |
RhoA multiple sclerosis experimental autoimmune encephalomyelitis T-cell neuroinflammation |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.01235/full |
work_keys_str_mv |
AT albamanresaarraut rhoadrivestcellactivationandencephalitogenicpotentialinananimalmodelofmultiplesclerosis AT flemmingfrydjohansen rhoadrivestcellactivationandencephalitogenicpotentialinananimalmodelofmultiplesclerosis AT cordbrakebusch rhoadrivestcellactivationandencephalitogenicpotentialinananimalmodelofmultiplesclerosis AT shohrehissazadehnavikas rhoadrivestcellactivationandencephalitogenicpotentialinananimalmodelofmultiplesclerosis AT henrikhasseldam rhoadrivestcellactivationandencephalitogenicpotentialinananimalmodelofmultiplesclerosis |
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1724853515798446080 |