The Chitinase-Like Protein YKL-40 Modulates Cystic Fibrosis Lung Disease

Andreas Hector,Matthias Griese,Ernst Eber,Carmen Casaulta,Marcus A Mall,Oliver Eickelberg,Alexander Bohla,Dominik Hartl,Olaf Eickmeier,Elisabeth Kieninger,Ines Mack,Philipp Latzin,Stefan Zielen,Matthias Kappler,Nikolaus Rieber,Ali Ö Yildirim,Michael S D Kormann,Zhe Zhou,Barbara Koller

doi:10.1371/journal.pone.0024399

Abstract

The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.

Highlights

Chronic lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients [1]
YKL-40 levels in CF sputa and CF sera showed a broad range of detection from levels similar to healthy control levels up to 30-fold higher levels in CF patients compared to healthy controls (Figure 1A right graph).YKL-40 serum levels correlated positively with YKL-40 sputum levels in both CF patients (r = 0.69, p,0.01) and, to a lesser extent, healthy control individuals (r = 0.42, p,0.05)
Consistent with human CF lung disease, protein levels of the murine YKL-40 homologue breast regression protein of 39 kDa (BRP-39) were highly increased in bronchoalveolar lavage fluid (BALF) from bENaC-Tg mice compared to BALF from WT mice (Figure 1B)

Summary

Introduction

Chronic lung disease determines the morbidity and mortality of cystic fibrosis (CF) patients [1]. CF lung disease is characterized by a nonresolving neutrophilic inflammation with impaired antibacterial killing and proteolytic destruction of pulmonary tissue [2]. But they express chitinases and chitinaselike proteins (CLP). Both chitinases and CLP belong to the 18glycosyl-hydrolase family, including acidic mammalian chitinase (AMCase), chitotriosidase, oviductin, YKL-40 in humans, while YM-1, YM-2, AMCase, oviductin, and breast regression protein (BRP-39) have been described in mice. CLPs bind chitin, but do not have enzymatic chitinase activity due to mutations in their highly conserved putative enzyme sites [3]. The prototypical CLP YKL-40 (YKL for the first three N-terminal residues of a 40 kDa protein, termed human cartilage glycoprotein (HcGP)-39)

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