Proteomics

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The integrin linked kinase is required for chemokine-triggered high affinity conformation of the leukocyte β2-integrin LFA-1The integrin linked kinase is required for chemokine-triggered high affinity conformation of the leukocyte β2-integrin LFA-1


ABSTRACT: Invasion of leukocytes, including neutrophils, in response to injury or infection relies on the orchestrated activation of integrins. The neutrophil integrin lymphocyte function-associated antigen-1 (LFA-1) has been implicated in the regulation of leukocyte adhesion by binding 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 tail of the β2-integrin. How the integrin linked kinase (ILK) affects activation of β2-integrins in leukocytes is currently unknown. Here, utilizing in vitro microfluidic adhesion chambers with conformation specific antibodies for neutrophil-like HL-60 cells, we show that knockdown of ILK reduces the conformational change of β2-integrins to the H+ conformation. Consequently, ILK-deficient mice show defects of leukocyte adhesion and recruitment in a chemokine and integrin-dependent cremaster muscle model and in a clinically relevant model of renal-ischemia-reperfusion-injury. Absence of protein kinase C (PKC)-α, which is known to phosphorylate Kindlin-3, reproduces such phenotype in bone marrow chimeric mice. ILK is required for chemokine-induced upregulation of PKC-α activity. Mass spectrometry analysis and western blot analyses revealed a stimulation- and ILK-dependent phosphorylation of kindlin-3 upon activation. Our data thus show that ILK impacts kindlin-3-dependent conformational activation of LFA-1, thus contributing to an inflammatory response.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil

DISEASE(S): Inflammation

SUBMITTER: Hannes Drexler  

LAB HEAD: Hannes C. A. Drexler

PROVIDER: PXD017088 | Pride | 2020-07-20

REPOSITORIES: Pride

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