Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Roland Immler
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Ina Rohwedder
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Valerio Lupperger
Institute of AI for Health, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
Johannes Pfabe
Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Mariano Gonzalez Pisfil
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Anna Yevtushenko
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Thomas Vogl
Institute of Immunology, University of Muenster, Muenster, Germany
Institute of Immunology, University of Muenster, Muenster, Germany
Melanie Salvermoser
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Steffen Dietzel
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Institute of AI for Health, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
Barbara Walzog
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
Walter Brendel Center of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig-Maximilians-University, Planegg-Martinsried, München, Germany
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 caused dysregulated Ca2+ signatures in activated neutrophils resulting in reduced Ca2+ availability at the formed LFA-1/F-actin clusters with defective β2 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 S100a9-/- compared to wildtype (WT) neutrophils, making S100a9-/- cells more susceptible to detach under flow, thereby preventing efficient neutrophil recruitment and extravasation into inflamed tissue.
