New Insights into Neutrophil Recruitment

January 8, 2025

The team around Prof. Sperandio, PD Dr. Monika Prünster and Dr. Matteo Napoli has uncovered a novel function of the protein heterodimer S100A8/A9 in neutrophils, the most abundant white blood cells in the human circulation, which play a critical role in innate immune responses. Their findings reveal how this protein influences calcium signalling, cytoskeletal dynamics and neutrophil recruitment to inflamed tissues, shedding light on its potential as a therapeutic target in inflammatory diseases.

Neutrophils are rapidly mobilised from the bloodstream into the tissue in response to sterile inflammation or infection. During this process, a coordinated interaction between activated endothelial cells and circulating neutrophils initiates the "leukocyte recruitment cascade", allowing neutrophils to migrate to affected tissues. S100A8/A9 is actively secreted during leukocyte recruitment and the extracellular protein functions as alarmin associated with pro-inflammatory effects.

This study focuses on the intracellular role of S100A8/A9 and demonstrates that genetic deletion of S100A9 in mice disrupted calcium signalling and impaired cytoskeletal rearrangements, cell polarisation and spreading. As a result, S100A8/A9-deficient neutrophils were unable to maintain firm adhesion under flow and were less able to migrate into inflamed tissue. These findings identify the cytosolic S100A8/A9 complex as a central player in the inflammatory recruitment of neutrophils. It orchestrates key processes that enable neutrophils to respond effectively to inflammation while maintaining the balance of the immune response.

Excessive neutrophil influx is a hallmark of many acute and chronic inflammatory diseases, and targeting S100A8/A9 may provide a means to mitigate tissue damage caused by excessive immune cell recruitment. From both a mechanistic and methodological point of view, this work is an important piece of the puzzle towards a better understanding of how neutrophils function in inflammation.

The study has been supported by the German Research Foundation (DFG) collaborative research grants SFB914, TRR-332 and TRR-359 and driven forward by the expertise and resources provided by the in-house core facilities for Flow Cytometry and Bioimaging.

Link to publication: https://elifesciences.org/articles/96810