Tensile force transmitted through LFA-1 bonds mechanoregulate neutrophil inflammatory response.
Recruitment of leukocytes to sites of acute inflammation is guided by spatial and temporal cues that ensure appropriate cell numbers infiltrate the tissue at precise locations to protect it from infection and initiate repair. On inflamed endothelium, neutrophil rolling via selectins elicits cytosolic calcium release from endoplasmic reticulum (ER)-stores that are synergistic with chemokine signaling to activate formation of high affinity (HA) LFA-1 bonds to ICAM-1, which is necessary to anchor cells against the drag force of blood flow. Bond tension on LFA-1 within the area of adhesive contact with endothelium elicits calcium entry through calcium release-activated calcium channel protein 1 (Orai-1) membrane channels that in turn activate neutrophil shape change and migration. We hypothesized that mechanotransduction via LFA-1 is mediated by assembly of a cytosolic molecular complex consisting of Kindlin-3, receptor for activated C kinase 1 (RACK1), and Orai1. Initiation of Ca2+ flux at sites of adhesive contact required a threshold level of shear stress and increased with the magnitude of bond tension transduced across as few as 200 HA LFA-1. A sequential mechanism triggered by force acting on LFA-1/Kindlin-3 precipitated dissociation of RACK1, which formed a concentration gradient above LFA-1 bond clusters. This directed translocation of ER proximal to Orai1, where binding of inositol 1,4,5-triphosphate receptor type 1 and activation via stromal interaction molecule 1 elicited Ca flux and subsequent neutrophil shape change and motility. We conclude that neutrophils sense adhesive traction on LFA-1 bonds on a submicron scale to direct calcium influx, thereby ensuring sufficient shear stress of blood flow is present to trigger cell arrest and initiate transmigration at precise regions of vascular inflammation.
['Morikis|Vasilios A|VA|', 'Masadeh|Eman|E|', 'Simon|Scott I|SI|0000-0003-1186-6611']
D006801:Humans D007249:Inflammation D018799:Intercellular Adhesion Molecule-1 D016169:Lymphocyte Function-Associated Antigen-1 D040542:Mechanotransduction, Cellular D008565:Membrane Proteins D009363:Neoplasm Proteins D009504:Neutrophils D000071740:ORAI1 Protein D000075370:Receptors for Activated C Kinase D013718:Tensile Strength
mechanotransduction kindlin-3 RACK1 calcium flux outside-in signaling