Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment

Napoli, M.; Immler, R.; Rohwedder, I.; Lupperger, V.; Pfabe, J.; Gonzalez Pisfil, M.; Yevtushenko, A.; Vogl, T.; Roth, J.; Salvermoser, M.; Dietzel, S.; Slak Rupnik, M.; Marr, C.; Walzog, B.; Sperandio, M.; Pruenster, M.

doi:10.1101/2024.04.16.589738

bioRxiv · 10.1101/2024.04.16.589738

Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment

Napoli, M.·Immler, R.·Rohwedder, I.·Lupperger, V.·Pfabe, J.·Gonzalez Pisfil, M.·Yevtushenko, A.·Vogl, T.·Roth, J.·Salvermoser, M.·Dietzel, S.·Slak Rupnik, M.·Marr, C.·Walzog, B.·Sperandio, M.·Pruenster, M.

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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 (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

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Napoli, M., Immler, R., Rohwedder, I., Lupperger, V., Pfabe, J., Gonzalez Pisfil, M., Yevtushenko, A., Vogl, T., Roth, J., Salvermoser, M., Dietzel, S., Slak Rupnik, M., Marr, C., Walzog, B., Sperandio, M., Pruenster, M.. 2024-04-22. Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment. https://doi.org/10.1101/2024.04.16.589738

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