L-selectin mechanochemistry restricts neutrophil priming in vivo

Nature Communications
Zhenghui LiuRodger P McEver

Abstract

Circulating neutrophils must avoid premature activation to prevent tissue injury. The leukocyte adhesion receptor L-selectin forms bonds with P-selectin glycoprotein ligand-1 (PSGL-1) on other leukocytes and with peripheral node addressin (PNAd) on high endothelial venules. Mechanical forces can strengthen (catch) or weaken (slip) bonds between biological molecules. How these mechanochemical processes influence function in vivo is unexplored. Here we show that mice expressing an L-selectin mutant (N138G) have altered catch bonds and prolonged bond lifetimes at low forces. Basal lymphocyte homing and neutrophil recruitment to inflamed sites are normal. However, circulating neutrophils form unstable aggregates and are unexpectedly primed to respond robustly to inflammatory mediators. Priming requires signals transduced through L-selectin N138G after it engages PSGL-1 or PNAd. Priming enhances bacterial clearance but increases inflammatory injury and enlarges venous thrombi. Thus, L-selectin mechanochemistry limits premature activation of neutrophils. Our results highlight the importance of probing how mechanochemistry functions in vivo.

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Citations

Apr 12, 2018·Journal of Innate Immunity·Scott D KobayashiFrank R DeLeo
Jan 22, 2018·Cell and Tissue Research·Aleksandar Ivetic
Jan 1, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yu Gang LiuYuan Zhuang
Nov 30, 2019·Biomolecular Concepts·Stefano LancellottiRaimondo De Cristofaro
Feb 7, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jarmila KralovaTomas Brdicka
Aug 4, 2018·Clinical Rheumatology·T KuretA Hočevar
Jun 14, 2018·European Journal of Clinical Investigation·Katja L VogtAlison M Condliffe
May 30, 2019·Frontiers in Immunology·Aleksandar IveticSamuel James Hart
Nov 21, 2018·Cell and Tissue Research·R A PoltavtsevaE V Svirshchevskaya

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Methods Mentioned

BETA
PMA
PCR
flow cytometry
lavage
light microscopy

Software Mentioned

NIS
Elements
ImageJ

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