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

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

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/84923295755

U2 - 10.1038/ncomms6359

DO - 10.1038/ncomms6359

M3 - Article

C2 - 25348463

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 5359

ER -