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

Morrison, Vicky Louise and James, Martyn John and Grzes, Katarzyna and Cook, Peter and Glass, David Gavin and Savinko, Terhi and Lek, Hwee San and Gawden-Bone, Christian and Watts, Colin and Millington, Owain Richard and MacDonald, Andrew Scott and Fagerholm, Susanna Carola (2014) Loss of ​beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype. Nature Communications, 5. 5359. ISSN 2041-1723 (https://doi.org/10.1038/ncomms6359)

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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.


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 ORCID logoORCID: https://orcid.org/0000-0002-3026-6550, MacDonald, Andrew Scott and Fagerholm, Susanna Carola;