TY - JOUR
T1 - Vascular surveillance by haptotactic blood platelets in inflammation and infection
AU - Nicolai, Leo
AU - Schiefelbein, Karin
AU - Lipsky, Silvia
AU - Leunig, Alexander
AU - Hoffknecht, Marie
AU - Pekayvaz, Kami
AU - Raude, Ben
AU - Marx, Charlotte
AU - Ehrlich, Andreas
AU - Pircher, Joachim
AU - Zhang, Zhe
AU - Saleh, Inas
AU - Marel, Anna Kristina
AU - Löf, Achim
AU - Petzold, Tobias
AU - Lorenz, Michael
AU - Stark, Konstantin
AU - Pick, Robert
AU - Rosenberger, Gerhild
AU - Weckbach, Ludwig
AU - Uhl, Bernd
AU - Xia, Sheng
AU - Reichel, Christoph Andreas
AU - Walzog, Barbara
AU - Schulz, Christian
AU - Zheden, Vanessa
AU - Bender, Markus
AU - Li, Rong
AU - Massberg, Steffen
AU - Gaertner, Florian
N1 - Funding Information:
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.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19515-0
DO - 10.1038/s41467-020-19515-0
M3 - Article
C2 - 33188196
AN - SCOPUS:85095945727
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5778
ER -