Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis

Katerina D Samara,Eleni Bibaki,George Margaritopoulos,Nikolaos Tzanakis,Eleni D Lagoudaki,Panagiotis Pantelidis,Katerina M Antoniou,Ismini Lasithiotaki,Anastasios V Koutsopoulos,Eliza Tsitoura,Athol U Wells,Athina Trachalaki,Nikolaos M Siafakas

doi:10.1186/s12931-017-0692-9

Abstract

BackgroundIncreased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear.MethodsWe evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified.ResultsPADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA-ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs).ConclusionsThese results suggest that the citrullination pathway is upregulated in IPF and in RA-ILD.

Highlights

Increased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity
PADI4 expression in BAL cells PADI4 mRNA transcripts were higher in rheumatoid arthritis associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) compared to controls (p = 0.005 and p = 0.019) (Fig. 1a and Table 2)
Since the control group, consisted exclusively of smokers, we performed a second analysis with ever smokers from each disease group and observed that PADI4 levels remained significantly higher in Rheumatoid arthritis (RA)-ILD and IPF compared to controls (Kruskal-Wallis test, p = 0.005) (Table 2)

Summary

Introduction

Increased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear. Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic polyarthritis of the small joints and is thought to be driven by antibodies against citrullinated proteins (ACPAs). Citrullination is a post-translational modification of the amino acid arginine into citrulline. It is a Ca2+ dependent reaction, catalyzed by peptidylarginine deiminases (PADIs) [4]. PADI4 polymorphisms leading to higher enzyme levels have been associated with RA susceptibility and HRCT abnormalities in lungs [8]. PADI4 is mainly expressed in macrophages, neutrophils, and eosinophils and triggers neutrophil extracellular traps

Methods

Results

Conclusion