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Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration.

ABSTRACT: 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.

SUBMITTER: Xu W

PROVIDER: S-EPMC2947797 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration.

Xu Wenwen W 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

Immunity 20100901 3

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- ...[more]

PMID: 20850356

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Project description:Introduction: The acute phase protein pentraxin 3 (PTX3) is known for its anti-inflammatory effects through downregulating neutrophil transmigration during peripheral inflammation. Furthermore, we have previously demonstrated a neuroprotective and neuroreparative effect of PTX3 after cerebral ischaemia. Here we investigated, to our knowledge for the first time, the role of PTX3 in neutrophil transmigration and neurotoxicity following lipopolysaccharide (LPS)-induced cerebral inflammation and cerebral ischaemia. Methods: Neutrophil transmigration through interleukin-1? (IL-1?) activated brain endothelium and neurotoxicity of neutrophils isolated from wild-type (WT) or PTX3 knock-out (KO) mice was assessed in vitro. Primary cortical neuronal death after treatment with transmigrated neutrophils was quantified by lactate dehydrogenase (LDH) assay. Cerebral inflammation or ischemia was induced in WT and PTX3 KO mice via intrastriatal LPS injection or by transient middle cerebral artery occlusion (MCAo) respectively. Subsequent neutrophil infiltration in the brain was assessed by immunohistochemistry and the expression of pro-inflammatory cytokines interleukin-6 (IL-6) and IL-1? by enzyme-linked immunosorbent assay (ELISA). Results: Neutrophils isolated from WT mice after intrastriatal LPS injection transmigrated significantly more through IL-1? activated brain endothelium compared to neutrophils from PTX3 KO mice. Transmigrated WT and PTX3 KO neutrophils were significantly more neurotoxic than corresponding non-transmigrated neutrophils; however, no significant differences in neurotoxicity between genotypes were observed. PTX3 reduced the number of transmigrated neutrophils to the brain after intrastriatal LPS injection. Furthermore, PTX3 KO mice showed significantly increased levels of neutrophils in the brain after LPS administration or in the ischaemic hemisphere after MCAo, compared to WT mice. Conclusion: Our study shows that PTX3 regulates neutrophil transmigration in the CNS during neuroinflammation, demonstrating the potential of PTX3 as an effective therapeutic target in neuroinflammatory conditions.

Dataset Information

Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration.

Publications

Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration.

Similar Datasets

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