Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials

Our plain-English summary of Induction of protein citrullination and auto-antibodies production in murine exposed to nickel nanomaterials, by B.M. Mohamed, N.T. Boyle, A. Schinwald, et al (Scientific Reports, 2018).

The study

• Authors: B.M. Mohamed, N.T. Boyle, A. Schinwald, B. Murer, R. Ward, O.K. Mahfoud, T. Rakovich, K. Crosbie-Staunton, S.G. Gray, K. Donaldson, Y. Volkov, A. Prina-Mello
• Journal: Scientific Reports
• Published: 2018;8(1):679
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Citrullination, or the post-translational deimination of polypeptide-bound arginine, is involved in several pathological processes in the body, including autoimmunity and tumorigenesis. Recent studies have shown that nanomaterials can trigger protein citrullination, which might constitute a common pathogenic link to disease development. Here we demonstrated auto-antibody production in serum of nanomaterials-treated mice. Citrullination-associated phenomena and PAD levels were found to be elevated in nanomaterials -treated cell lines as well as in the spleen, kidneys and lymph nodes of mice, suggesting a systemic response to nanomaterials injection, and validated in human pleural and pericardial malignant mesothelioma (MM) samples. The observed systemic responses in mice exposed to nanomaterials support the evidence linking exposure to environmental factors with the development of autoimmunity responses and reinforces the need for comprehensive safety screening of nanomaterials. Furthermore, these nanomaterials induce pathological processes that mimic those observed in Pleural MM, and therefore require further investigations into their carcinogenicity.

In plain English

This laboratory study tested whether engineered nickel nanomaterials trigger protein citrullination, a protein change linked to autoimmune disease. The authors exposed two human cell lines to short and long nickel nanowires. They also injected nanowires or nickel nanoparticles into the pleural (chest) cavity of mice and examined the mice after 24 hours and 2 weeks. In the cells, citrullination rose with dose. In the mice, citrullinated proteins appeared in blood, and antibodies against citrullinated proteins (anti-CCP3) were found at two weeks. Lymph nodes showed more cells with citrullinated proteins, and cells containing the enzymes PAD2 and PAD4 also increased. No citrullination was detected in kidneys. No animals or cells were exposed to asbestos. Separately, the authors stained tissue from four pleural mesothelioma patients with known asbestos exposure, four mesothelioma cases without such history, and two benign pleural samples. They reported very weak staining in benign tissue and strong PAD4 and citrullination staining in the asbestos-exposed cases. The authors concluded that nickel nanowires evoke immune responses similar to those observed for fibre-type materials such as asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining cell-line experiments, a mouse experiment using intrapleural injection of nickel nanomaterials, and immunostaining of archived human mesothelioma and benign pleural tissue
• Who was studied: Human lung epithelial (A549) and phagocytic (THP-1) cell lines; female C57BL/6 mice (40 reported, injected in groups of three); human tissue from 4 pleural malignant mesothelioma patients with known asbestos exposure (Mestre, Venice, Italy archives), plus a commercial tissue microarray with 4 pleural or pericardial mesothelioma cases without a history of asbestos exposure and 2 benign pleural tissue cases
• Exposure: Engineered nickel nanowires with average lengths of 4.3 plus or minus 1.0 µm (short) and 24.0 plus or minus 7.2 µm (long), and commercial nickel nanoparticles (mean dry diameter 15.0 nm), given to cells in culture and injected intrapleurally into mice, with saline vehicle as control. Asbestos appears only as the patients' exposure history; no fiber type is named.
• Main results:
  • In both cell lines, nickel nanowires induced protein citrullination in a significant dose-dependent manner, with maximum effect at the highest dose (10 µg/ml)
  • In the sera of mice exposed to short nanowires, long nanowires and nanoparticles, distinct citrullinated protein bands (40 to 60 kDa) were detected
  • Sera from exposed mice collected two weeks after exposure showed significant levels of anti-CCP3 antibody
  • In lymph node tissue of exposed mice, the number of cells with citrullinated proteins increased significantly compared with vehicle control
  • In spleen tissue, cells positive for citrullinated proteins were elevated 24 hours after exposure, and this elevation was attenuated by 2 weeks
  • No protein citrullination was detected in kidney tissue of exposed mice
  • Cells stained for PAD4 increased significantly in all examined tissues (lymph node, spleen, kidney) of exposed mice compared with vehicle; PAD2-positive cells also increased in all nanomaterial-treated groups
  • In human tissue, staining for PAD2, PAD4 and citrullinated proteins was very weak in benign pleural tissue and increased in pleural and pericardial mesothelioma without asbestos exposure history
  • Strong staining for PAD4 and citrullinated proteins was found in pleural mesothelioma tissue from patients with known asbestos exposure
• The authors' conclusion: The authors concluded that their findings provide evidence that engineered nickel nanowires evoke immune responses similar to those observed for environmental fibre-type nanomaterials such as asbestos. They also suggested PAD2, PAD4 and citrullination as potential markers for early-stage mesothelioma and called for further carcinogenicity studies of these nanomaterials.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Pericardial, Mesothelioma.

Related studies

• Length-dependent pathogenic effects of nickel nanowires in the lungs and the peritoneal cavity — C.A. Poland, F. Byrne, et al. (2012)
• Auto-antibodies to β-F1-ATPase and vimentin in malignant mesothelioma — J. Creaney, I.M. Dick, et al. (2011)
• p53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer — J. Schneider, P. Presek, et al. (1999)
• Spontaneous lysosomal enzyme secretion by a murine macrophage-like cell line — W. Jessup, R.T. Dean (1980)
• Use of back-scatter electron signals to visualise cell/nanowires interactions in vitro and in vivo; frustrated phagocytosis of long fibres in macrophages and compartmentalisation in mesothelial cells in vivo — A. Schinwald, K. Donaldson (2012)
• Autoantibodies from mice exposed to Libby amphibole asbestos bind SSA/Ro52-enriched apoptotic blebs of murine macrophages — D.J. Blake, S.A. Wetzel, et al. (2008)

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