Thesis defense Max Grönloh
Where white blood cells wander: homing in on leukocyte extravasation hotspots
On 27 March 2024 (11:00 AM) Max Grönloh defended his PhD thesis 'Where white blood cells wander: homing in on leukocyte extravasation hotspots' at the University of Amsterdam.
Promotor
Prof JD van Buul PhD
Copromotor
J Goedhart PhD
Venue
Aula, University of Amsterdam
Abstract
To properly resolve infections, white blood cells must exit blood vessels via leukocyte transendothelial migration. The cells comprising the inner layer of a blood vessel – endothelial cells – respond to infections in the underlying tissues by presenting adhesion proteins and chemotactic cues for circulating leukocytes . Interestingly, leukocytes do not exit the vasculature at random sites but utilise so-called ‘ extravasation hotspots ’. In this thesis, mechanisms underlying the formation of hotspots are proposed, and their physiological relevance in protecting the vascular barrier is demonstrated. We experimentally show that the heterogenous expression of adhesion molecule ICAM-1 acts as a marker for neutrophil extravasation hotspots . After ICAM-1-mediated adhesion, ICAM-2 coordinates the ability of adhered neutrophils to withstand the forces of blood flow. Next, we show that the adhesion of neutrophils results in the induction of apically protruding adhesive filopodia, which facilitates subsequently arriving neutrophils in their adhesion to inflamed endothelial cells . Moreover, endothelial cells link the transmigration dynamics of leukocytes derived from the innate and adaptive immunity. By adhering to endothelial cells , neutrophils induce the translation of pre-existing CXCL12 mRNA, which is presented to CD8+ T cells and enhances their ability to undergo transendothelial migration at the same extravasation hotspot. Subsequently, we provide a dataset that explored heterogeneity within the inflamed endothelial monolayer. This dataset allowed us to form novel hypotheses regarding the formation of hotspots that could be tested in future projects. Lastly, we provide a biological explanation for the effectiveness of tocilizumab treatment in severe COVID-19.
