Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment
S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions. Mechanistically, genetic deletion of S100A9 in mice (Mrp14-/-, functional S100a8/a9-/-) caused dysregulated Ca2+ signatures in activated neutrophils resulting in reduced Ca2+ availability at the formed LFA-1/F-actin clusters with defective {beta}2 integrin outside-in signaling during post-arrest modifications. Consequently, we observed impaired cytoskeletal rearrangement, cell polarization and spreading, as well as cell protrusion formation in Mrp14-/- compared to WT neutrophils, making Mrp14-/- cells more susceptible to detach under flow, thereby preventing efficient neutrophil recruitment and extravasation into inflamed tissue. One-sentence summaryintracellular S100A8/A9 is indispensable for firm leukocyte adhesion under flow