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 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 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.
Authors
- Mariano Gonzalez Pisfil (ORCID: https://orcid.org/0000-0002-5008-8763)
- Johannes Pfabe (ORCID: https://orcid.org/0000-0003-3665-8739)
- Ina Rohwedder
- Melanie Salvermoser
- Monika Pruenster (ORCID: https://orcid.org/0000-0001-8573-6866)
- Marjan Slak Rupnik (ORCID: https://orcid.org/0000-0002-3744-4882)
- Roland Immler (ORCID: https://orcid.org/0000-0002-4086-7528)
- Thomas Vogl (ORCID: https://orcid.org/0000-0001-9669-7479)
- Steffen Dietzel (ORCID: https://orcid.org/0000-0001-5725-3242)
- Carsten Marr (ORCID: https://orcid.org/0000-0003-2154-4552)
- Valerio Lupperger (ORCID: https://orcid.org/0000-0002-0112-2283)
- Matteo Napoli (ORCID: https://orcid.org/0000-0002-8197-9374)
- Anna Yevtushenko
- Johannes Roth (ORCID: https://orcid.org/0000-0001-7035-8348)
- Markus Sperandio (ORCID: https://orcid.org/0000-0002-7689-3613)
- Barbara Walzog (ORCID: https://orcid.org/0000-0001-7729-6565)
Institutions
- Center for Environmental Health (US)
- Helmholtz Zentrum München (DE)
- Institute of Immunology (HR)
- Centre of Experimental Medicine of the Slovak Academy of Sciences (SK)
- Medical University of Vienna (AT)
Publication Details
- Journal
- eLife
- Published
- 2024-12-19
- DOI
- https://doi.org/10.7554/elife.96810.3
- Citations
- 1
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Deutsche Forschungsgemeinschaft