Local factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration
- 17 February 2022
- journal article
- research article
- Published by Wiley in The Journal of Pathology
- Vol. 257 (1), 29-38
- https://doi.org/10.1002/path.5867
Abstract
Activation of the alternative complement pathway is an initiating event in the pathology of Age-related Macular Degeneration (AMD). Unchecked complement activation leads to the formation of a pro-lytic pore, the Membrane Attack Complex (MAC). MAC deposition is observed on the choriocapillaris of AMD patients and likely causes lysis of choroidal endothelial cells (CECs). Complement factor H (FH, encoded by the gene CFH), is an inhibitor of complement. Both loss of function of FH and reduced choroidal levels of FH have been reported in AMD. It is plausible that reduced local FH availability promotes MAC deposition on CECs. FH is produced primarily in the liver; however, cells including the retinal pigment epithelium can produce FH locally. We hypothesized that CECs produce FH locally to protect against MAC deposition. We aimed to investigate the effect of reduced FH levels in the choroid to determine whether increasing local FH could protect CECs from MAC deposition. We demonstrated that siRNA knockdown of FH (CFH) in human immortalized CECs results in increased MAC deposition. We generated AMD iPSC-derived CECs and found that overexpression of FH protects against MAC deposition. These results suggest that local CEC-produced FH protects against MAC deposition, and that increasing local FH protein may be beneficial in limiting MAC deposition in AMD.Funding Information
- Elmer and Sylvia Sramek Charitable Trust
- Fight for Sight UK (PD‐20005)
- National Institutes of Health (EY‐024605, EY‐025580)
This publication has 54 references indexed in Scilit:
- Association between CFH Y402H Polymorphism and Age Related Macular Degeneration in North Indian CohortPLOS ONE, 2013
- Elevated membrane attack complex in human choroid with high risk complement factor H genotypesExperimental Eye Research, 2011
- Choriocapillaris Vascular Dropout Related to Density of Drusen in Human Eyes with Early Age-Related Macular DegenerationInvestigative Ophthalmology & Visual Science, 2011
- Heparan Sulfate, Including That in Bruch’s Membrane, Inhibits the Complement Alternative Pathway: Implications for Age-Related Macular DegenerationThe Journal of Immunology, 2010
- Impaired Binding of the Age-related Macular Degeneration-associated Complement Factor H 402H Allotype to Bruch's Membrane in Human Retina*Online Journal of Public Health Informatics, 2010
- Complement: a key system for immune surveillance and homeostasisNature Immunology, 2010
- Oxidative Stress Renders Retinal Pigment Epithelial Cells Susceptible to Complement-mediated InjuryOnline Journal of Public Health Informatics, 2009
- Translational Mini-Review Series on Complement Factor H: Renal diseases associated with complement factor H: novel insights from humans and animalsClinical and Experimental Immunology, 2008
- Translational Mini-Review Series on Complement Factor H: Genetics and disease associations of human complement factor HClinical and Experimental Immunology, 2007
- Complement Factor H Polymorphism in Age-Related Macular DegenerationScience, 2005