Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis

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.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0692-9) contains supplementary material, which is available to authorized users.

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…The responsible enzymes were later identified as Changes in citrullination occur in several pathological conditions such as autoimmune disorders and chronic inflammation-related diseases, including periodontitis, rheumatoid arthritis, atherosclerosis, and diabetes [13][14][15] (see Alghamdi, M. et al [13] for a detailed review on the intrinsic role of citrullination in autoimmune disorders and Olsen, I. et al, [14] for a detailed review on citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis, and Alzheimer's disease). Altered levels of citrullination have also been shown in neurological disorders and prion diseases, [16,17] and respiratory disorders [18,19]. Citrullination can generate new epitopes, which can produce new autoantigens linked to altered immune responses (see [20] for a review on citrullination and autoimmunity).…”

Insights into the study and origin of the citrullinome in rheumatoid arthritis

“…Several tissue sources have been studied to examine this hypothesis including bronchoalveolar lavage (BAL), bronchial mucosa, lung tissue, and/or sputum from a variety of individuals including healthy non‐smokers and smokers, patients with RA‐associated interstitial lung disease (RA‐ILD), RA‐associated interstitial pneumonia (RA‐IP), idiopathic IP, non‐RA patients with chronic obstructive pulmonary disease (non‐RA COPD), RA patients without pulmonary symptoms, and RA‐free subjects at risk for RA . Among these studies, only two addressed citrullination in the lung by MS.…”

“…GrB, granzyme B; APC, antigen-presenting cell and RA-free subjects at risk for RA. 57,[133][134][135][136][137][138][139][140][141][142] Among these studies, only two addressed citrullination in the lung by MS. In lung tissue from non-RA COPD, MS was only applied to study citrullination of α-enolase and vimentin, but only confirmed citrullination in vimentin.…”

Exacerbation of symptomatic arthritis by cigarette smoke in experimental arthritis

“…The constituent proteins of synovial membrane (i.e. vimentin, collagen, and fibronectin) are easily citrullinated, leading to increased levels of anti-CCP antibodies [9][10][11].…”