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Rho-GTPase dependen...
Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis
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- Malmhäll-Bah, Eric (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Andersson, Karin, 1972 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Erlandsson, Malin, 1972 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Akula, Murali K (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Centre for Molecular and Translational Medicine,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Brisslert, Mikael, 1974 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Wiel, Clotilde, 1987 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Wallenberg Centre for Molecular and Translational Medicine,Institute of Clinical Sciences, Department of Surgery
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- El Zowalaty, Ahmed E (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Wallenberg Centre for Molecular and Translational Medicine,Institute of Clinical Sciences, Department of Surgery
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- Sayin, Volkan I., 1983 (author)
- Gothenburg University,Göteborgs universitet,Wallenberg Centre for Molecular and Translational Medicine,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
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- Bergö, Martin O., 1970 (author)
- Karolinska Institutet,Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Centre for Molecular and Translational Medicine,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Bokarewa, Maria, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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(creator_code:org_t)
- Elsevier BV, 2022
- 2022
- English.
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In: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 130
- Related links:
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https://gup.ub.gu.se...
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Abstract
Subject headings
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- Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4(+) T cells from GLC mice (CD4(+)GLCs). Spleen and joint draining lymph nodes (dLN) CD4(+)GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4(+)GLCs presented a complete signature of GARP(+)NRP1(+)IKZF2(+)FOXP3(+) regulatory T cells (Tregs) of thymic origin. Activation of the beta-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4(+) cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4(+) cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4(+)GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthri-togenic phenotype.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Keyword
- Rho-GTPases
- HOXA
- Thymic T regs
- Arthritis
- beta-integrin
- t-cells
- activation
- migration
- rac1
- wnt
- hox
- differentiation
- prenylation
- inhibition
- expression
- Immunology
Publication and Content Type
- ref (subject category)
- art (subject category)
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Malmhäll-Bah, Er ...
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Andersson, Karin ...
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Erlandsson, Mali ...
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Akula, Murali K
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Brisslert, Mikae ...
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Wiel, Clotilde, ...
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El Zowalaty, Ahm ...
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Sayin, Volkan I. ...
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Bergö, Martin O. ...
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Bokarewa, Maria, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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MEDICAL AND HEAL ...
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Journal of Autoi ...
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University of Gothenburg
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Karolinska Institutet