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 Cheng Qi, Alex P. Hunyor, Steven A Krilis, Bill M Giannakopoulos

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

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 proinflammatory 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.

Original languageEnglish
Pages (from-to)49016-49032
Number of pages17
JournalOncotarget
Volume8
Issue number30
DOIs
Publication statusPublished - 2017
Externally publishedYes

Keywords

  • Complement factor H
  • Macular degeneration
  • Nitrosative stress
  • Retina

Cite this

Krilis, Matthew ; Qi, Miao ; Madigan, Michele C. ; Wong, Jason W.H. ; Abdelatti, Mahmoud ; Guymer, Robyn H. ; Whitelock, John ; McCluskey, Peter ; Zhang, Peng ; Qi, Jian Cheng ; Hunyor, Alex P. ; Krilis, Steven A ; Giannakopoulos, Bill M. / Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration. In: Oncotarget. 2017 ; Vol. 8, No. 30. pp. 49016-49032.
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title = "Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration",
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 proinflammatory 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.",
keywords = "Complement factor H, Macular degeneration, Nitrosative stress, Retina",
author = "Matthew Krilis and Miao Qi and Madigan, {Michele C.} and Wong, {Jason W.H.} and Mahmoud Abdelatti and Guymer, {Robyn H.} and John Whitelock and Peter McCluskey and Peng Zhang and Qi, {Jian Cheng} and Hunyor, {Alex P.} and Krilis, {Steven A} and Giannakopoulos, {Bill M}",
year = "2017",
doi = "10.18632/oncotarget.14940",
language = "English",
volume = "8",
pages = "49016--49032",
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Krilis, M, Qi, M, Madigan, MC, Wong, JWH, Abdelatti, M, Guymer, RH, Whitelock, J, McCluskey, P, Zhang, P, Qi, JC, Hunyor, AP, Krilis, SA & Giannakopoulos, BM 2017, 'Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration', Oncotarget, vol. 8, no. 30, pp. 49016-49032. https://doi.org/10.18632/oncotarget.14940

Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration. / Krilis, Matthew; Qi, Miao; Madigan, Michele C.; Wong, Jason W.H.; Abdelatti, Mahmoud; Guymer, Robyn H.; Whitelock, John; McCluskey, Peter; Zhang, Peng; Qi, Jian Cheng; Hunyor, Alex P.; Krilis, Steven A; Giannakopoulos, Bill M.

In: Oncotarget, Vol. 8, No. 30, 2017, p. 49016-49032.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration

AU - Krilis, Matthew

AU - Qi, Miao

AU - Madigan, Michele C.

AU - Wong, Jason W.H.

AU - Abdelatti, Mahmoud

AU - Guymer, Robyn H.

AU - Whitelock, John

AU - McCluskey, Peter

AU - Zhang, Peng

AU - Qi, Jian Cheng

AU - Hunyor, Alex P.

AU - Krilis, Steven A

AU - Giannakopoulos, Bill M

PY - 2017

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N2 - 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 proinflammatory 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.

AB - 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 proinflammatory 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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