FGF23 signaling impairs neutrophil recruitment and host defense during CKD
Jan Rossaint, Jessica Oehmichen, Hugo Van Aken, Stefan Reuter, Hermann J. Pavenstädt, Melanie Meersch, Mark Unruh, Alexander Zarbock
Jan Rossaint, Jessica Oehmichen, Hugo Van Aken, Stefan Reuter, Hermann J. Pavenstädt, Melanie Meersch, Mark Unruh, Alexander Zarbock
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Research Article Nephrology

FGF23 signaling impairs neutrophil recruitment and host defense during CKD

Abstract

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 β2 integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rap1. 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.

Authors

Jan Rossaint, Jessica Oehmichen, Hugo Van Aken, Stefan Reuter, Hermann J. Pavenstädt, Melanie Meersch, Mark Unruh, Alexander Zarbock

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Figure 6

Selectin-mediated slow rolling and chemokine-induced arrest is impaired in human patients with CKD.

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Selectin-mediated slow rolling and chemokine-induced arrest is impaired ...
(A and B) Heparinised whole blood samples were obtained from healthy volunteers and CKD stage 3–5 patients and perfused through coated flow chambers, and the rolling velocity on E-selectin and E-selectin/ICAM-1 (A) or P-selectin and P-selectin/ICAM-1 (B) was analyzed by video microscopy (n = 8–13). (C and D) Whole blood samples from healthy volunteers were incubated with FGF23, and the rolling velocity in flow chambers with E-selectin and E-selectin/ICAM-1 (C) or P-selectin and P-selectin/ICAM-1 (D) was analyzed (n = 4). (E) To investigate chemokine-induced arrest, whole blood samples from healthy volunteers and CKD stage 3–5 patients were perfused through flow chambers coated with P-selectin/ICAM-1 or P-selectin/ICAM-1/IL-8 (n = 8–13). (F) Whole blood samples from healthy volunteers were incubated with FGF23, and the chemokine-induced arrest in flow chambers coated with P-selectin/ICAM-1 or P-selectin/ICAM-1/IL-8 was analyzed (n = 4). *P < 0.05, ANOVA plus Bonferroni testing in A, B, and E or 2-tailed t test in C, D, and F.