title: Loss of beta2-integrin-mediated cytoskeletal linkage reprogrammes dendritic cells to a mature migratory phenotype.
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.
authors.affiliation: 1] Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK [2] Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Vicky Louise
authors.initials: VL
authors.lastname: Morrison
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Martyn John
authors.initials: MJ
authors.lastname: James
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Grzes
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Cook
authors.affiliation: 1] Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK [2] Institute of Photonics, SUPA, University of Strathclyde, Glasgow G4 0NW, UK.
authors.forename: David Gavin
authors.initials: DG
authors.lastname: Glass
authors.affiliation: Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.affiliation: Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
authors.forename: Hwee San
authors.initials: HS
authors.lastname: Lek
authors.affiliation: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Gawden-Bone
authors.affiliation: College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Watts
authors.affiliation: Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK.
authors.forename: Owain Richard
authors.initials: OR
authors.lastname: Millington
authors.affiliation: Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester M13 9NT, UK.
authors.forename: Andrew Scott
authors.initials: AS
authors.lastname: MacDonald
authors.affiliation: 1] Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK [2] Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
authors.forename: Susanna Carola
authors.initials: SC
authors.lastname: Fagerholm
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018821:CD18 Antigens / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D000199:Actins; D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C527818:kindlin-3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse