Fibroblast growth factor 23 and Klotho contribute to airway inflammation

Abstract

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 klotho-mediated FGFR activation delineates a pathophysiologic mechanism in COPD remains unclear. We hypothesized 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 IL-1β release via klotho-independent FGFR4-mediated activation of phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling. 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. In conclusion, 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.

Alpha‐Klotho, a critical protein for lung health, is not expressed in normal lung

“…On the other hand, Kuro‐o and colleagues discovered that αKlotho could not detect αKlotho transcript in the intact lung, a finding independently reproduced by our group . Despite the absence of mRNA, αKlotho protein expression was reported in lungs and large airways by several groups using commercial antibodies . The discrepant in vitro and in vivo results, complicated by uncertain sensitivity and specificity of the various anti‐αKlotho antibodies used in different studies, significantly impede progress in the understanding of αKlotho biology.…”

“…The highly enriched αKlotho content in human induced pluripotent stem cell secretome significantly contributes to protection of lung cells and lungs from hyperoxic injury . Multiple laboratories have shown direct or indirect αKlotho actions in the lung using in vitro systems . Cumulative literature unequivocally supports a pivotal cytoprotective role of αKlotho in the lung.…”

Transcriptional profiling of the murine airway response to acute ozone exposure

“…Down regulation of Oxtr has been associated with behavioral changes after diesel exhaust exposure in mice (WIN-SHWE 2014), and may bind to RAGE (receptor for advanced glycation endproducts) (YAMAMOTO 2019), a receptor involved in recognizing damageassociated molecular patterns (DAMPs) that has been implicated in inflammatory responses to acute lung injury (GRIFFITHS AND MCAULEY 2008;BLONDONNET et al 2017). Fgf23 (fibroblast growth factor 23) followed a concentration-response expression pattern after both 1 and 2 ppm O3 exposure (1 ppm FC: 14.9, 2 ppm FC: 48.5), and has been shown to promote airway inflammation and release of IL-1β, in the context of chronic obstructive pulmonary disease (KRICK et al 2018). Finally, Ptx3, the gene encoding pentraxin 3, was highly upregulated after 2 ppm O3 exposure (FC 17.2).…”

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

“…Further renal conditions including fibrosis , albuminuria and autosomal dominant polycystic kidney disease (ADPKD) are associated with elevated FGF23 levels. Also, impaired liver function and lung disease stimulate FGF23 production. Patients with heart failure or atherosclerosis have higher FGF23 levels.…”