GPVI and Thromboxane Receptor on Platelets Promote Proinflammatory Macrophage Phenotypes during Cutaneous Inflammation.
Platelets are well known for their role in hemostasis but are also increasingly recognized for their supporting role in innate immune responses. Here, we studied the role of platelets in the development of peripheral inflammation and found that platelets colocalize with macrophages in the inflamed tissue outside of blood vessels in different animal models for cutaneous inflammation. Collagen-treatment of macrophages isolated from paws during zymosan-induced inflammation induced thromboxane synthesis through the platelet-expressed collagen receptor glycoprotein VI. Deletion of glycoprotein VI or its downstream effector thromboxane A2 receptor (TP) reduced zymosan-induced mechanical allodynia without altering macrophage recruitment or formation of macrophage/platelet complexes. Instead, macrophages in inflamed paws of glycoprotein VI- and TP-deficient mice exhibited an increased expression of anti-inflammatory markers and synthesized less proinflammatory mediators (prostaglandin E2and IL6). TP expression on platelets was necessary to mediate increased prostaglandin E2and IL6 synthesis, whereas TP expression on macrophages was sufficient to decrease the expression of the anti-inflammatory macrophage marker CD206, showing that TP activation on platelets and macrophages regulates different aspects of macrophage activation.
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Sandra
S
Pierre
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Bona
B
Linke
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Jing
J
Suo
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Neda
N
Tarighi
Institut für Klinische Neuroanatomie, Neuroscience Center, Goethe-Universität Frankfurt, Frankfurt, Germany.
Domenico
D
Del Turco
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Dominique
D
Thomas
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Nerea
N
Ferreiros
Universität Würzburg, Institut für Experimentelle Biomedizin, Universitätsklinikum und Rudolf-Virchow-Zentrum für Experimentelle Biomedizin, Würzburg, Germany.
David
D
Stegner
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Stefanie
S
Frölich
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Marco
M
Sisignano
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany; Fraunhofer Institute of Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt, Germany.
Sascha
S
Meyer Dos Santos
Fraunhofer Institute of Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt, Germany.
Natasja
N
deBruin
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany.
Rolf M
RM
Nüsing
Institut für Klinische Neuroanatomie, Neuroscience Center, Goethe-Universität Frankfurt, Frankfurt, Germany.
Thomas
T
Deller
Universität Würzburg, Institut für Experimentelle Biomedizin, Universitätsklinikum und Rudolf-Virchow-Zentrum für Experimentelle Biomedizin, Würzburg, Germany.
Bernhard
B
Nieswandt
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany; Fraunhofer Institute of Molecular Biology and Applied Ecology-Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt, Germany.
Gerd
G
Geisslinger
Institut für Klinische Pharmakologie, pharmazentrum frankfurt, ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt, Germany. Electronic address: Scholich@em.uni-frankfurt.de.
Klaus
K
Scholich
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D003094:Collagen / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D007249:Inflammation; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism*; D012867:Skin / Q000473:pathology*; D013928:Thromboxane A2 / Q000378:metabolism
D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C098341:platelet membrane glycoprotein VI; D013928:Thromboxane A2; D003094:Collagen