Oncotarget

Research Papers:

Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration

Matthew Krilis, Miao Qi, Michele C. Madigan, Jason W.H. Wong, Mahmoud Abdelatti, Robyn H. Guymer, John Whitelock, Peter McCluskey, Peng Zhang, Jian Qi, Alex P. Hunyor, Steven A. Krilis and Bill Giannakopoulos _

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Oncotarget. 2017; 8:49016-49032. https://doi.org/10.18632/oncotarget.14940

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Abstract

Matthew Krilis1,*, Miao Qi2,*, Michele C. Madigan1,3, Jason W. H. Wong4, Mahmoud Abdelatti2, Robyn H. Guymer5, John Whitelock6, Peter McCluskey1, Peng Zhang2,7, Jian Qi2, Alex P. Hunyor1, Steven A. Krilis2,* and Bill Giannakopoulos2,8,*

1Save Sight Institute, University of Sydney and Sydney Eye Hospital, Sydney, NSW, Australia

2Department of Infectious Diseases, Immunology and Sexual Health and Department of Medicine, St George Hospital, University of New South Wales, Sydney, NSW, Australia

3School of Optometry and Vision Science, University of New South Wales, Sydney, NSW, Australia

4Prince of Wales Clinical School, University of New South Wales, Lowy Cancer Research Centre, Sydney, NSW, Australia

5Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia

6Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW, Australia

7Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Tianjin, China

8Department of Rheumatology, St George Hospital, Sydney, NSW, Australia

*These authors have contributed equally to this work

Correspondence to:

Bill Giannakopoulos, email: bill.giannakopoulos@unsw.edu.au

Keywords: macular degeneration, complement factor H, nitrosative stress, retina

Received: November 11, 2016     Accepted: December 27, 2016     Published: February 01, 2017

ABSTRACT

Nitrosative stress has been implicated in the pathogenesis of age related macular degeneration (AMD). Tyrosine nitration is a unique type of post translational modification that occurs in the setting of inflammation and nitrosative stress. To date, the significance and functional implications of tyrosine nitration of complement factor H (CFH), a key complement regulator in the eye has not been explored, and is examined in this study in the context of AMD pathogenesis.

Sections of eyes from deceased individuals with AMD (n = 5) demonstrated the presence of immunoreactive nitrotyrosine CFH. We purified nitrated CFH from retinae from 2 AMD patients. Mass spectrometry of CFH isolated from AMD eyes revealed nitrated residues in domains critical for binding to heparan sulphate glycosaminoglycans (GAGs), lipid peroxidation by-products and complement (C) 3b.

Functional studies revealed that nitrated CFH did not bind to lipid peroxidation products, nor to the GAG of perlecan nor to C3b. There was loss of cofactor activity for Factor I mediated cleavage of C3b with nitrated CFH compared to non-nitrated CFH. CFH inhibits, but nitrated CFH significantly potentiates, the secretion of the pro-inflammatory and angiogenic cytokine IL-8 from monocytes that have been stimulated with lipid peroxidation by-products. AMD patients (n = 30) and controls (n = 30) were used to measure plasma nitrated CFH using a novel ELISA. AMD patients had significantly elevated nitrated CFH levels compared to controls (p = 0.0117). These findings strongly suggest that nitrated CFH contributes to AMD progression, and is a target for therapeutic intervention.


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