L-selectin mechanochemistry restricts neutrophil priming in vivo

Zhenghui Liu,Cheng Zhu,Nan Zhang,Ying Wang,Rodger P Mcever,Longbiao Yao,Tadayuki Yago,Lijun Xia,Padmaja Mehta-D’Souza,Sumith R Panicker

doi:10.1038/ncomms15196

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.

Highlights

Circulating neutrophils must avoid premature activation to prevent tissue injury
bone marrow (BM) neutrophils from N138G mice expressed slightly less L-selectin (Fig. 1b), slightly more integrin aMb2 (Mac-1) (Fig. 1c), and normal levels of integrin aLb2 (LFA-1) and several other glycoproteins (Supplementary Fig. 3)
We have shown that altering the mechanochemistry of an adhesion receptor profoundly affects its functions in vivo

Summary

Introduction

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. Force-regulated transitions between catch and slip bonds influence cell adhesion, morphology and signalling[1,2,3]. In vitro studies support the hypothesis that catch bonds limit leukocyte adhesion to vessels during stasis and prevent aggregation of freeflowing leukocytes[14], which express both L-selectin and PSGL-1. Under both conditions, L-selectin bonds would have shorter lifetimes because little force is exerted on them. How L-selectin mechanochemistry acts in vivo has not been tested

Methods

Results

Conclusion