Nicolai, Leo; Schiefelbein, Karin; Lipsky, Silvia; Leunig, Alexander; Hoffknecht, Marie; Pekayvaz, Kami; Raude, Ben; Marx, Charlotte; Ehrlich, Andreas; Pircher, Joachim; Zhang, Zhe; Saleh, Inas
Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets.
We thank Sebastian Helmer, Nicole Blount, Christine Mann, and Beate Jantz for technical assistance; Hellen Ishikawa-Ankerhold for help and advice; Michael Sixt for critical discussions. This study was supported by the DFG SFB 914 (S.M. [B02 and Z01], K.Sch. [B02], B.W. [A02 and Z03], C.A.R. [B03], C.S. [A10], J.P. [Gerok position]), the DFG SFB 1123 (S.M. [B06]), the DFG FOR 2033 (S.M. and F.G.), the German Center for Cardiovascular Research (DZHK) (Clinician Scientist Program [L.N.], MHA 1.4VD [S.M.], Postdoc Start-up Grant, 81×3600213 [F.G.]), FP7 program (project 260309, PRESTIGE [S.M.]), FöFoLe project 1015/1009 (L.N.), FöFoLe project 947 (F.G.), the Friedrich-Baur-Stiftung project 41/16 (F.G.), and LMUexcellence NFF (F.G.). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 833440) (S.M.). F.G. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 747687.
Nicolai L, Schiefelbein K, Lipsky S, et al. Vascular surveillance by haptotactic blood platelets in inflammation and infection. Nature Communications. 2020;11. doi:10.1038/s41467-020-19515-0
Nicolai, L., Schiefelbein, K., Lipsky, S., Leunig, A., Hoffknecht, M., Pekayvaz, K., … Gärtner, F. R. (2020). Vascular surveillance by haptotactic blood platelets in inflammation and infection. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-020-19515-0
Nicolai, Leo, Karin Schiefelbein, Silvia Lipsky, Alexander Leunig, Marie Hoffknecht, Kami Pekayvaz, Ben Raude, et al. “Vascular Surveillance by Haptotactic Blood Platelets in Inflammation and Infection.” Nature Communications. Springer Nature, 2020. https://doi.org/10.1038/s41467-020-19515-0.
L. Nicolai et al., “Vascular surveillance by haptotactic blood platelets in inflammation and infection,” Nature Communications, vol. 11. Springer Nature, 2020.
Nicolai L, Schiefelbein K, Lipsky S, Leunig A, Hoffknecht M, Pekayvaz K, Raude B, Marx C, Ehrlich A, Pircher J, Zhang Z, Saleh I, Marel A-K, Löf A, Petzold T, Lorenz M, Stark K, Pick R, Rosenberger G, Weckbach L, Uhl B, Xia S, Reichel CA, Walzog B, Schulz C, Zheden V, Bender M, Li R, Massberg S, Gärtner FR. 2020. Vascular surveillance by haptotactic blood platelets in inflammation and infection. Nature Communications. 11, 5778.
Nicolai, Leo, et al. “Vascular Surveillance by Haptotactic Blood Platelets in Inflammation and Infection.” Nature Communications, vol. 11, 5778, Springer Nature, 2020, doi:10.1038/s41467-020-19515-0.
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