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

The actin cytoskeleton has been reported to restrict signaling 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. H...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258606/
https://www.ncbi.nlm.nih.gov/pubmed/25348463
http://dx.doi.org/10.1038/ncomms6359
Descripción
Sumario:The actin cytoskeleton has been reported to restrict signaling 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 signaling, and to the induction of a transcriptional program 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 signaling, survival, maturation and migration in myeloid cells and thereby contribute to immune homeostasis in vivo.