title: SRF is required for neutrophil migration in response to inflammation.
abstract: 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 Srf(fl/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.
authors.affiliation: Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center.
authors.forename: Ashley
authors.initials: A
authors.lastname: Taylor
authors.forename: Wenwen
authors.initials: W
authors.lastname: Tang
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Bruscia
authors.forename: Ping-Xia
authors.initials: PX
authors.lastname: Zhang
authors.forename: Aiping
authors.initials: A
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Gaines
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halene
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics* / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000235:genetics* / Q000503:physiopathology; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026362:Serum Response Factor / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000199:Actins; D018925:Chemokines; D016023:Integrins; D026362:Serum Response Factor; D009240:N-Formylmethionine Leucyl-Phenylalanine