A β2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

• Published in: Frontiers in immunology Vol. 10; p. 1138
• Main Authors: Guenther, Carla, Faisal, Imrul, Uotila, Liisa M, Asens, Marc Llort, Harjunpää, Heidi, Savinko, Terhi, Öhman, Tiina, Yao, Sean, Moser, Markus, Morris, Stephan W, Tojkander, Sari, Fagerholm, Susanna Carola
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 28.05.2019
• Subjects: adhesion; dendritic cells; Immunology; LAD-III; MKL-1; MRTF-A; SRF; traction force; MKL-1; LAD-III; dendritic cells; MRTF-A; SRF; adhesion
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.01138

β2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of β -integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the β2-integrin (TTT/AAA-β2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-β2-integrin KI dendritic cells, which leads to a failure of MRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of β2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of β2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.