FGF23 signaling impairs neutrophil recruitment and host defense during CKD

Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstaedt HJ, Meersch M, Unruh M, Zarbock A

Forschungsartikel (Zeitschrift) | Peer reviewed

Zusammenfassung

Chronic kidney disease (CKD) has been associated with impaired host response and increased susceptibility to infections. Leukocyte recruitment during inflammation must be tightly regulated to protect the host against pathogens. FGF23 levels are increased in blood during CKD, and levels of this hormone have been associated with a variety of adverse effects in CKD patients. Here, we have shown that CKD impairs leukocyte recruitment into inflamed tissue and host defense in mice and humans. FGF23 neutralization during CKD in murine models restored leukocyte recruitment and host defense. Intravital microscopy of animals with chronic kidney failure showed that FGF23 inhibits chemokine-activated leukocyte arrest on the endothelium, and downregulation of FGF receptor 2 (FGFR2) on PMNs rescued host defense in these mice. In vitro, FGF23 inhibited PMN adhesion, arrest under flow, and transendothelial migration. Mechanistically, FGF23 binding to FGFR2 counteracted selectin- and chemokine-triggered beta(2) integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rapt. Moreover, knockdown of PKA abolished the inhibitory effect of FGF23 on integrin activation. Together, our data reveal that FGF23 acts directly on PMNs and dampens host defense by direct interference with chemokine signaling and integrin activation.

Details zur Publikation

FachzeitschriftJournal of Clinical Investigation (J Clin Invest)
Jahrgang / Bandnr. / Volume126
Ausgabe / Heftnr. / Issue3
Seitenbereich962-974
StatusVeröffentlicht
Veröffentlichungsjahr2016
Sprache, in der die Publikation verfasst istEnglisch
DOI10.1172/JCI83470

Autor*innen der Universität Münster

Meersch-Dini, Melanie
Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
Pavenstädt, Hermann-Joseph
Medizinische Klinik D (Med D)
Reuter, Stefan Johannes
Medizinische Klinik D (Med D)
Rossaint, Jan Peter
Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
Van Aken, Hugo K.
Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
Zarbock, Alexander
Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie