Focal adhesion kinase regulates pathogen-killing capability and life span of neutrophils via mediating both adhesion-dependent and -independent cellular signals.
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.
Kasorn
Anongnard
A
Department of Community Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand.
Alcaide
Pilar
P
Jia
Yonghui
Y
Subramanian
Kulandayan K
KK
Sarraj
Bara
B
Li
Yitang
Y
Loison
Fabien
F
Hattori
Hidenori
H
Silberstein
Leslie E
LE
Luscinskas
William F
WF
Luo
Hongbo R
HR
D000818:Animals; D020013:Calcium Signaling; D002448:Cell Adhesion / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016923:Cell Death; D002633:Chemotaxis; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D010538:Peritonitis / Q000276:immunology; D010587:Phagocytosis; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D015815:Cell Adhesion Molecules; D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D051416:Focal Adhesion Protein-Tyrosine Kinases