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Focal Adhesion Kinase Regulates Pathogen-Killing Capability and Life Span of Neutrophils via Mediating Both Adhesion-Dependent and -Independent Cellular Signals¹

Anongnard Kasorn^*, Pilar Alcaide, Yonghui Jia, Kulandayan K. Subramanian, Bara Sarraj, Yitang Li, Fabien Loison, Hidenori Hattori, Leslie E. Silberstein, William F. Luscinskas and Hongbo R. Luo^2,

*Department of Community Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand; Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, and Department of Lab Medicine, Children's Hospital Boston, Boston, MA 02115; Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Division of Organ Transplant, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

Various neutrophil functions such as phagocytosis, superoxide production, and survival are regulated by integrin signaling. Despite the essential role of focal adhesion kinase (FAK) in mediating this signaling pathway, its exact function in neutrophils is ill defined. In this study, we investigated the role of FAK in neutrophils using a myeloid-specific conditional FAK knockout mouse. As reported in many other cell types, FAK is required for regulation of focal adhesion dynamics when neutrophils adhere to fibronectin or ICAM-1. Adhesion on VCAM-1-coated surfaces and chemotaxis after adhesion were not altered in FAK null neutrophils. In addition, we observed significant reduction in NADPH oxidase-mediated superoxide production and complement-mediated phagocytosis in FAK null neutrophils. As a result, these neutrophils displayed decreased pathogen killing capability both in vitro and in vivo in a mouse peritonitis model. In adherent cells, the defects associated with FAK deficiency are likely due to suppression of phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3) signaling and chemoattractant-elicited calcium signaling. Disruption of FAK also reduced chemoattractant-elicited superoxide production in suspended neutrophils in the absence of cell adhesion. This may be solely caused by suppression of PtdIns(3,4,5)P3 signaling in these cells, because the fMLP-elicited calcium signal was not altered. Consistent with decreased PtdIns(3,4,5)P3/Akt signaling in FAK null neutrophils, we also observed accelerated spontaneous death in these cells. Taken together, our results revealed previously unrecognized roles of FAK in neutrophil function and provided a potential therapeutic target for treatment of a variety of infectious and inflammatory diseases.

²Address correspondence and reprint requests to Dr. Hongbo R. Luo, Karp Family Research Building, Room 10214, Boston, MA 02115. E-mail address: Hongbo.Luo{at}childrens.harvard.edu

¹ B.S. is supported by National Institutes of Health Training Grant HL066987, and H.L. is supported by National Institutes of Health Grants HL085100, AI076471, and GM076084 and a Research Scholar Grant from American Cancer Society.