FGF23 signaling impairs neutrophil recruitment and host defense during CKD
Jan Rossaint ... Mark Unruh, Alexander Zarbock
Jan Rossaint ... Mark Unruh, Alexander Zarbock
Published March 1, 2016
Citation Information: J Clin Invest. 2016;126(3):962-974. doi:10.1172/JCI83470.
View: Text | PDF
Categories: 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

×

Figure 1

Neutrophil recruitment and host defense during pneumonia is decreased in mice with chronic kidney failure.

Options: View larger image (or click on image) Download as PowerPoint
Neutrophil recruitment and host defense during pneumonia is decreased in...
CKD was achieved in mice by 5/6-nephrectomy, and pneumonia was induced by E. coli instillation after 10 days. (A–D) Twenty-four hours after inducing pneumonia, neutrophils were counted in the BAL (A), and CFUs were analyzed in the BAL (B), lung tissue (C), and spleen (D) of sham-operated and CKD mice (n = 4). (E–H) Pneumonia was induce in sham mice and CKD mice, and sham mice after pretreatment with FGF23 and neutrophils were counted in the BAL (F), lung tissue (G), and spleen (H) (n = 4). (I–P) Pneumonia was also induced in CKD mice after injection of a neutralizing FGF23 antibody (3 mg/kg body weight) or isotype control (I–L) and mice transplanted with control or FGFR2-KD BM (M–P) (n = 4). (Q and R) Survival curves of sham-operated animals and CKD animals (Q) and sham-operated animals and CKD animals treated with isotype or FGF23 neutralizing Ab (R). *P < 0.05, ANOVA plus Bonferroni testing in E–L or 2-tailed t test in A–D and M–P.