[HTML][HTML] FGF23 signaling impairs neutrophil recruitment and host defense during CKD

J Rossaint, J Oehmichen, H Van Aken… - The Journal of …, 2016 - Am Soc Clin Investig
J Rossaint, J Oehmichen, H Van Aken, S Reuter, HJ Pavenstädt, M Meersch, M Unruh
The Journal of clinical investigation, 2016Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation