Matteo Napoli, Roland Immler, Ina Rohwedder, Valerio Lupperger, Johannes Pfabe, Mariano Gonzalez Pisfil, Anna Yevtushenko, Thomas Vogl, Johannes Roth, Melanie Salvermoser, Steffen Dietzel, Marjan Slak Rupnik, Carsten Marr, Barbara Walzog, Markus Sperandio, Monika Pruenster
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引用次数: 0
Abstract
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.
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