SRF is required for neutrophil migration in response to inflammation

• Published in: Blood 2014-05, Vol.123 (19), p.3027-3036
• Main Authors: Taylor, Ashley, Tang, Wenwen, Bruscia, Emanuela M., Zhang, Ping-Xia, Lin, Aiping, Gaines, Peter, Wu, Dianqing, Halene, Stephanie
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - drug effects; Actin Cytoskeleton - metabolism; Actins - metabolism; Animals; Blotting, Western; Cell Adhesion - genetics; Cell Adhesion - physiology; Cell Movement - genetics; Cell Movement - physiology; Chemokines - metabolism; Gene Expression - drug effects; Inflammation - genetics; Inflammation - physiopathology; Integrins - genetics; Integrins - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophils - drug effects; Neutrophils - metabolism; Neutrophils - pathology; Phagocytes, Granulocytes, and Myelopoiesis; Polymerization - drug effects; Reverse Transcriptase Polymerase Chain Reaction; Serum Response Factor - deficiency; Serum Response Factor - genetics; Serum Response Factor - physiology; Signal Transduction - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-06-507582

Serum response factor (SRF) is a ubiquitously expressed transcription factor and master regulator of the actin cytoskeleton. We have previously shown that SRF is essential for megakaryocyte maturation and platelet formation and function. Here we elucidate the role of SRF in neutrophils, the primary defense against infections. To study the effect of SRF loss in neutrophils, we crossed Srffl/fl mice with select Cre-expressing mice and studied neutrophil function in vitro and in vivo. Despite normal neutrophil numbers, neutrophil function is severely impaired in Srf knockout (KO) neutrophils. Srf KO neutrophils fail to polymerize globular actin to filamentous actin in response to N-formyl-methionine-leucine-phenylalanine, resulting in significantly disrupted cytoskeletal remodeling. Srf KO neutrophils fail to migrate to sites of inflammation in vivo and along chemokine gradients in vitro. Polarization in response to cytokine stimuli is absent and Srf KO neutrophils show markedly reduced adhesion. Integrins play an essential role in cellular adhesion, and although integrin expression levels are maintained with loss of SRF, integrin activation and trafficking are disrupted. Migration and cellular adhesion are essential for normal cell function, but also for malignant processes such as metastasis, underscoring an essential function for SRF and its pathway in health and disease. •SRF is essential for neutrophil migration in part by regulation of integrin homeostasis.•Several genes located on chromosome 5q are part of the SRF signaling pathway implicating dysfunction of SRF in myelodysplasia.