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Napoli, Matteo; Immler, Roland; Rohwedder, Ina; Lupperger, Valerio; Pfabe, Johannes; Gonzalez Pisfil, Mariano; Yevtushenko, Anna; Vogl, Thomas; Roth, Johannes; Salvermoser, Melanie; Dietzel, Steffen; Slak Rupnik, Marjan; Marr, Carsten; Walzog, Barbara; Sperandio, Markus; Pruenster, Monika (2024): Cytosolic S100A8/A9 promotes Ca 2+ supply at LFA-1 adhesion clusters during neutrophil recruitment. eLife. ISSN 2050-084X (Submitted)



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 Ca 2+ signatures in activated neutrophils resulting in reduced Ca 2+ availability at the formed LFA-1/F-actin clusters with defective β 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 summary: intracellular S100A8/A9 is indispensable for firm leukocyte adhesion under flow

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