Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype

Vicky Louise Morrison, Martyn John James, Katarzyna Grzes, Peter Cook, David Gavin Glass, Terhi Savinko, Hwee San Lek, Christian Gawden-Bone, Colin Watts, Owain Richard Millington, Andrew Scott MacDonald, Susanna Carola Fagerholm

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The actin cytoskeleton has been reported to restrict signalling in resting immune cells. Beta2-integrins, which mediate adhesion and cytoskeletal organization, are emerging as negative regulators of myeloid cell-mediated immune responses, but the molecular mechanisms involved are poorly understood. Here, we show that loss of the interaction between beta2-integrins and kindlin-3 abolishes the actin-linkage of integrins and the GM-CSF receptor in dendritic cells. This leads to increased GM-CSF receptor/Syk signalling, and to the induction of a transcriptional programme characteristic of mature, migratory dendritic cells, accumulation of migratory dendritic cells in lymphoid organs, and increased Th1 immune responses in vivo. We observe increased GM-CSF responses and increased survival in neutrophils where the interaction between integrin and the cytoskeleton is disrupted. Thus, ligand-reinforced beta2-integrin tail interactions restrict cytokine receptor signalling, survival, maturation and migration in myeloid cells and thereby contribute to immune homeostasis in vivo.

LanguageEnglish
Article number5359
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 28 Oct 2014

Fingerprint

CD18 Antigens
phenotype
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
linkages
Dendritic Cells
Myeloid Cells
Phenotype
Integrins
Actins
cells
Cytokine Receptors
Granulocyte-Macrophage Colony-Stimulating Factor
Cytoskeleton
Actin Cytoskeleton
Neutrophils
Homeostasis
Adhesion
neutrophils
Ligands
homeostasis

Keywords

  • immunology
  • actin cytoskeleton
  • dendritic cells

Cite this

Morrison, V. L., James, M. J., Grzes, K., Cook, P., Glass, D. G., Savinko, T., ... Fagerholm, S. C. (2014). Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. Nature Communications, 5, [5359]. https://doi.org/10.1038/ncomms6359
Morrison, Vicky Louise ; James, Martyn John ; Grzes, Katarzyna ; Cook, Peter ; Glass, David Gavin ; Savinko, Terhi ; Lek, Hwee San ; Gawden-Bone, Christian ; Watts, Colin ; Millington, Owain Richard ; MacDonald, Andrew Scott ; Fagerholm, Susanna Carola. / Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. In: Nature Communications. 2014 ; Vol. 5.
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abstract = "The actin cytoskeleton has been reported to restrict signalling in resting immune cells. Beta2-integrins, which mediate adhesion and cytoskeletal organization, are emerging as negative regulators of myeloid cell-mediated immune responses, but the molecular mechanisms involved are poorly understood. Here, we show that loss of the interaction between beta2-integrins and kindlin-3 abolishes the actin-linkage of integrins and the GM-CSF receptor in dendritic cells. This leads to increased GM-CSF receptor/Syk signalling, and to the induction of a transcriptional programme characteristic of mature, migratory dendritic cells, accumulation of migratory dendritic cells in lymphoid organs, and increased Th1 immune responses in vivo. We observe increased GM-CSF responses and increased survival in neutrophils where the interaction between integrin and the cytoskeleton is disrupted. Thus, ligand-reinforced beta2-integrin tail interactions restrict cytokine receptor signalling, survival, maturation and migration in myeloid cells and thereby contribute to immune homeostasis in vivo.",
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Morrison, VL, James, MJ, Grzes, K, Cook, P, Glass, DG, Savinko, T, Lek, HS, Gawden-Bone, C, Watts, C, Millington, OR, MacDonald, AS & Fagerholm, SC 2014, 'Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype' Nature Communications, vol. 5, 5359. https://doi.org/10.1038/ncomms6359

Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. / Morrison, Vicky Louise; James, Martyn John; Grzes, Katarzyna; Cook, Peter; Glass, David Gavin; Savinko, Terhi; Lek, Hwee San; Gawden-Bone, Christian; Watts, Colin; Millington, Owain Richard; MacDonald, Andrew Scott; Fagerholm, Susanna Carola.

In: Nature Communications, Vol. 5, 5359, 28.10.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype

AU - Morrison, Vicky Louise

AU - James, Martyn John

AU - Grzes, Katarzyna

AU - Cook, Peter

AU - Glass, David Gavin

AU - Savinko, Terhi

AU - Lek, Hwee San

AU - Gawden-Bone, Christian

AU - Watts, Colin

AU - Millington, Owain Richard

AU - MacDonald, Andrew Scott

AU - Fagerholm, Susanna Carola

PY - 2014/10/28

Y1 - 2014/10/28

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AB - The actin cytoskeleton has been reported to restrict signalling in resting immune cells. Beta2-integrins, which mediate adhesion and cytoskeletal organization, are emerging as negative regulators of myeloid cell-mediated immune responses, but the molecular mechanisms involved are poorly understood. Here, we show that loss of the interaction between beta2-integrins and kindlin-3 abolishes the actin-linkage of integrins and the GM-CSF receptor in dendritic cells. This leads to increased GM-CSF receptor/Syk signalling, and to the induction of a transcriptional programme characteristic of mature, migratory dendritic cells, accumulation of migratory dendritic cells in lymphoid organs, and increased Th1 immune responses in vivo. We observe increased GM-CSF responses and increased survival in neutrophils where the interaction between integrin and the cytoskeleton is disrupted. Thus, ligand-reinforced beta2-integrin tail interactions restrict cytokine receptor signalling, survival, maturation and migration in myeloid cells and thereby contribute to immune homeostasis in vivo.

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