FGF23 signaling impairs neutrophil recruitment and host defense during CKD

J Clin Invest. 2016 Mar 1;126(3):962-74. doi: 10.1172/JCI83470. Epub 2016 Feb 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • CD18 Antigens / metabolism
  • Case-Control Studies
  • Female
  • Fibroblast Growth Factors / physiology*
  • HEK293 Cells
  • HL-60 Cells
  • Humans
  • Immunity, Cellular*
  • Leukocyte Rolling
  • Male
  • Mice, Inbred C57BL
  • Neutrophil Infiltration*
  • Neutrophils / physiology*
  • Pneumonia, Bacterial / immunology
  • Pneumonia, Bacterial / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Renal Insufficiency, Chronic / immunology*
  • Renal Insufficiency, Chronic / metabolism
  • Signal Transduction

Substances

  • CD18 Antigens
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • Fgfr2 protein, mouse
  • Receptor, Fibroblast Growth Factor, Type 2