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The integrin linked kinase is required for chemokine-triggered high affinity conformation of neutrophil beta2-integrin LFA1.

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Krenn,  Peter William
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Margraf, A., Germena, G., Drexler, H. C. A., Rossaint, J., Ludwig, N., Prystaj, B., et al. (2020). The integrin linked kinase is required for chemokine-triggered high affinity conformation of neutrophil beta2-integrin LFA1. Blood, 136(19), 2200-2205. doi:10.1182/blood.2020004948.


Cite as: http://hdl.handle.net/21.11116/0000-0007-86B9-1
Abstract
Neutrophil adhesion and extravasation into tissue at sites of injury or infection depend on binding of integrin lymphocyte function-associated antigen-1 (LFA-1) to ICAM-1 expressed on activated endothelial cells. The activation-dependent conformational change of LFA-1 to the high affinity conformation (H+) requires kindlin-3 binding to the beta2-integrin cytoplasmic domain. Here we show that genetic deletion of the known kindlin-interactor integrin linked kinase (ILK) impaired neutrophil adhesion and extravasation in the cremaster muscle and in a clinically relevant model of renal-ischemia-reperfusion injury. Utilizing in vitro microfluidic adhesion chambers and conformation specific antibodies, we show that knockdown of ILK in HL-60 cells reduces the conformational change of beta2-integrins to the H+ conformation. Mechanistically, we found that ILK is required for PKC membrane targeting and for chemokine-induced upregulation of its kinase activity. Moreover, PKC-alpha deficiency also results in impaired leukocyte adhesion in bone marrow chimeric mice. Mass spectrometric and western blot analyses revealed a stimulation- and ILK-dependent phosphorylation of kindlin-3 upon activation. In sum our data indicate an important role of ILK in kindlin-3-dependent conformational activation of LFA-1. Copyright © 2020 American Society of Hematology.