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 and Susanna Carola Fagerholm ()
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Vicky Louise Morrison: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Martyn John James: Institute of Biotechnology, University of Helsinki
Katarzyna Grzes: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Peter Cook: Manchester Collaborative Centre for Inflammation Research, University of Manchester
David Gavin Glass: Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde
Terhi Savinko: Institute of Biotechnology, University of Helsinki
Hwee San Lek: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee
Christian Gawden-Bone: College of Life Sciences, University of Dundee
Colin Watts: College of Life Sciences, University of Dundee
Owain Richard Millington: Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde
Andrew Scott MacDonald: Manchester Collaborative Centre for Inflammation Research, University of Manchester
Susanna Carola Fagerholm: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6359

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