Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration.
Neutrophils are important in innate immunity and acute inflammatory responses. However, the regulation of their recruitment to sites of inflammation has not been well characterized. Here, we investigated the kinase PIP5K1C and showed that PIP5K1C deficiency impaired neutrophil recruitment because of an adhesion defect. PIP5K1C regulated the adhesion through facilitating RhoA GTPase and integrin activation by chemoattractants. Integrins could induce polarization of an isoform of PIP5K1C, PIP5K1C-90, in neutrophils through intracellular vesicle transport independently of exogenous chemoattractant. PIP5K1C-90 polarization was required for polarized RhoA activation at uropods and provided an initial directional cue for neutrophil polarization on the endothelium. Importantly, the polarization was also required for circumventing the inhibition of lamellipodium formation by RhoA so that neutrophils could form leading edges required for transendothelial migration. Because integrins are not known to regulate neutrophil polarization, our study revealed a previously underappreciated role of integrin signaling in neutrophil regulation.
Xu
Wenwen
W
Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, China.
Wang
Ping
P
Petri
Björn
B
Zhang
Yong
Y
Tang
Wenwen
W
Sun
Le
L
Kress
Holger
H
Mann
Tom
T
Shi
Yan
Y
Kubes
Paul
P
Wu
Dianqing
D
D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000502:physiology; D016023:Integrins / Q000502:physiology*; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D022161:Transport Vesicles / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D016023:Integrins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein