TY - JOUR
T1 - Fibroblast growth factor 23 and Klotho contribute to airway inflammation
AU - Krick, Stefanie
AU - Grabner, Alexander
AU - Baumlin, Nathalie
AU - Yanucil, Christopher
AU - Helton, Scott
AU - Grosche, Astrid
AU - Sailland, Juliette
AU - Geraghty, Patrick
AU - Viera, Liliana
AU - Russell, Derek W.
AU - Wells, J. Michael
AU - Xu, Xin
AU - Gaggar, Amit
AU - Barnes, Jarrod
AU - King, Gwendalyn D.
AU - Campos, Michael
AU - Faul, Christian
AU - Salathe, Matthias
N1 - Funding Information:
Support statement: This work was supported by the Flight Attendant Medical Research Institute (YFAC152003 to S. Krick, YCSA113380 to P. Geraghty and CIA13033 to M. Salathe), the Cystic Fibrosis Foundation (CFF KRICK1610 to S. Krick and SALATH14G0 to M. Salathe), the American Heart Association (A. Grabner and C. Faul), the American Diabetes Association (C. Faul), the James and Esther King Florida Biomedical Research Program (5JK02 to M. Salathe) and the National Institutes of Health (R01HL128714 to C. Faul). Funding information for this article has been deposited with the Crossref Funder Registry.
Publisher Copyright:
© ERS 2018.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Circulating levels of fibroblast growth factor (FGF)23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-Klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and Klothomediated FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised that FGF23 can potentiate airway inflammation via Klotho-independent FGFR4 activation. FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients, and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model. Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in interleukin-1β release via Klotho-independent FGFR4-mediated activation of phospholipase Cy/nuclear factor of activated T-cells signalling. In addition, Klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of Klotho led to an attenuation of airway inflammation. Cigarette smoke induces airway inflammation by downregulation of Klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD.
AB - Circulating levels of fibroblast growth factor (FGF)23 are associated with systemic inflammation and increased mortality in chronic kidney disease. α-Klotho, a co-receptor for FGF23, is downregulated in chronic obstructive pulmonary disease (COPD). However, whether FGF23 and Klothomediated FGF receptor (FGFR) activation delineates a pathophysiological mechanism in COPD remains unclear. We hypothesised that FGF23 can potentiate airway inflammation via Klotho-independent FGFR4 activation. FGF23 and its effect were studied using plasma and transbronchial biopsies from COPD and control patients, and primary human bronchial epithelial cells isolated from COPD patients as well as a murine COPD model. Plasma FGF23 levels were significantly elevated in COPD patients. Exposure of airway epithelial cells to cigarette smoke and FGF23 led to a significant increase in interleukin-1β release via Klotho-independent FGFR4-mediated activation of phospholipase Cy/nuclear factor of activated T-cells signalling. In addition, Klotho knockout mice developed COPD and showed airway inflammation and elevated FGFR4 expression in their lungs, whereas overexpression of Klotho led to an attenuation of airway inflammation. Cigarette smoke induces airway inflammation by downregulation of Klotho and activation of FGFR4 in the airway epithelium in COPD. Inhibition of FGF23 or FGFR4 might serve as a novel anti-inflammatory strategy in COPD.
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U2 - 10.1183/13993003.00236-2018
DO - 10.1183/13993003.00236-2018
M3 - Article
C2 - 29748308
AN - SCOPUS:85049613179
VL - 52
JO - Scandinavian Journal of Respiratory Diseases
JF - Scandinavian Journal of Respiratory Diseases
SN - 0903-1936
IS - 1
M1 - 1800236
ER -