Sijia Cao1, Jay Ching Chieh Wang1, Jiangyuan Gao1, Matthew Wong1, Elliott To1, Valerie A White2, Jing Z Cui1, Joanne A Matsubara1. 1. Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 2. Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract
BACKGROUND/AIMS: The Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this polymorphism at the systemic level, but less is known of the associations in the outer retina of the genotyped eye. Here we investigate complement activation products and their role in nuclear factor (NF)-κB activation and gene expression of the NLRP3 inflammasome pathway. METHODS: Postmortem donor eyes were genotyped for the CFH Y402H polymorphism and assessed for complement C3a, C5a, interleukin (IL)-18 and tumour necrosis factor (TNF)-α. ARPE19 cells were stimulated basolaterally with C5a or TNF-α in polarised cultures. NF-κB activation was assessed with a reporter cell line. Gene expression of inflammasome-related (NLRP3, caspase-1, IL-1β and IL-18) and classic inflammatory (IL-6 and IL-8) genes was studied. The distribution of inflammasome products, IL-1β and IL-18, was studied in postmortem donor eyes with AMD pathologies. RESULTS: Eyes with the homozygous at-risk variant demonstrated higher levels of C5a, IL-18 and TNF-α in Bruch's membrane and choroid. C5a promoted NF-κB activation and upregulation of IL-18 in polarised ARPE19. TNF-α promoted NF-κB activation and gene expression of caspase-1, IL-1β, IL-18, IL-6 and IL-8, but downregulated NLRP3. In eyes with geographic atrophy, strong immunoreactivity was observed for inflammasome products IL-1β and IL-18 compared with age-matched controls. CONCLUSION: The at-risk polymorphism of the CFH Y402H may contribute to AMD disease process through increased complement and NF-κB activation, and the upregulation of IL-18, a product of inflammasome activation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND/AIMS: The Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this polymorphism at the systemic level, but less is known of the associations in the outer retina of the genotyped eye. Here we investigate complement activation products and their role in nuclear factor (NF)-κB activation and gene expression of the NLRP3 inflammasome pathway. METHODS: Postmortem donor eyes were genotyped for the CFH Y402H polymorphism and assessed for complement C3a, C5a, interleukin (IL)-18 and tumour necrosis factor (TNF)-α. ARPE19 cells were stimulated basolaterally with C5a or TNF-α in polarised cultures. NF-κB activation was assessed with a reporter cell line. Gene expression of inflammasome-related (NLRP3, caspase-1, IL-1β and IL-18) and classic inflammatory (IL-6 and IL-8) genes was studied. The distribution of inflammasome products, IL-1β and IL-18, was studied in postmortem donor eyes with AMD pathologies. RESULTS: Eyes with the homozygous at-risk variant demonstrated higher levels of C5a, IL-18 and TNF-α in Bruch's membrane and choroid. C5a promoted NF-κB activation and upregulation of IL-18 in polarised ARPE19. TNF-α promoted NF-κB activation and gene expression of caspase-1, IL-1β, IL-18, IL-6 and IL-8, but downregulated NLRP3. In eyes with geographic atrophy, strong immunoreactivity was observed for inflammasome products IL-1β and IL-18 compared with age-matched controls. CONCLUSION: The at-risk polymorphism of the CFH Y402H may contribute to AMD disease process through increased complement and NF-κB activation, and the upregulation of IL-18, a product of inflammasome activation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Authors: Gregory S Hageman; Don H Anderson; Lincoln V Johnson; Lisa S Hancox; Andrew J Taiber; Lisa I Hardisty; Jill L Hageman; Heather A Stockman; James D Borchardt; Karen M Gehrs; Richard J H Smith; Giuliana Silvestri; Stephen R Russell; Caroline C W Klaver; Irene Barbazetto; Stanley Chang; Lawrence A Yannuzzi; Gaetano R Barile; John C Merriam; R Theodore Smith; Adam K Olsh; Julie Bergeron; Jana Zernant; Joanna E Merriam; Bert Gold; Michael Dean; Rando Allikmets Journal: Proc Natl Acad Sci U S A Date: 2005-05-03 Impact factor: 11.205
Authors: Guangpu Shi; Siqi Chen; Wambui S Wandu; Osato Ogbeifun; Lindsey F Nugent; Arvydas Maminishkis; Samuel J H Hinshaw; Ignacio R Rodriguez; Igal Gery Journal: Invest Ophthalmol Vis Sci Date: 2015-02-12 Impact factor: 4.799
Authors: Daniel N Cortright; Robin Meade; Stephen M Waters; Bertrand L Chenard; James E Krause Journal: Curr Eye Res Date: 2009-01 Impact factor: 2.424
Authors: Ronald E Gangnon; Kristine E Lee; Barbara E K Klein; Sudha K Iyengar; Theru A Sivakumaran; Ronald Klein Journal: Arch Ophthalmol Date: 2012-09
Authors: Sarah L Doyle; Ema Ozaki; Kiva Brennan; Marian M Humphries; Kelly Mulfaul; James Keaney; Paul F Kenna; Arvydas Maminishkis; Anna-Sophia Kiang; Sean P Saunders; Emily Hams; Ed C Lavelle; Clair Gardiner; Padraic G Fallon; Peter Adamson; Peter Humphries; Matthew Campbell Journal: Sci Transl Med Date: 2014-04-02 Impact factor: 17.956
Authors: Luping Wang; Sarah Schmidt; Petra P Larsen; Johanna H Meyer; William R Roush; Eicke Latz; Frank G Holz; Tim U Krohne Journal: J Mol Med (Berl) Date: 2019-02-10 Impact factor: 4.599
Authors: Mara C Ebeling; Cody R Fisher; Rebecca J Kapphahn; Madilyn R Stahl; Shichen Shen; Jun Qu; Sandra R Montezuma; Deborah A Ferrington Journal: Cells Date: 2022-06-30 Impact factor: 7.666
Authors: Aniket Ramshekar; Haibo Wang; Eric Kunz; Christian Pappas; Gregory S Hageman; Brahim Chaqour; David B Sacks; M Elizabeth Hartnett Journal: FASEB J Date: 2021-07 Impact factor: 5.834
Authors: Christopher B Toomey; Michael Landowski; Mikael Klingeborn; Una Kelly; John Deans; Holly Dong; Ons Harrabi; Thomas Van Blarcom; Yik Andy Yeung; Ruslan Grishanin; John C Lin; Daniel R Saban; Catherine Bowes Rickman Journal: Invest Ophthalmol Vis Sci Date: 2018-02-01 Impact factor: 4.799
Authors: Tamar R Grossman; Michele Carrer; Lijiang Shen; Robert B Johnson; Lisa A Hettrick; Scott P Henry; Brett P Monia; Michael L McCaleb Journal: Mol Vis Date: 2017-08-10 Impact factor: 2.367