Journal article
Local Factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration
The Journal of pathology, Vol.257(1), pp.29-38
01/17/2022
DOI: 10.1002/path.5867
PMCID: PMC9007903
PMID: 35038170
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. This article is protected by copyright. All rights reserved.
Details
- Title: Subtitle
- Local Factor H production by human choroidal endothelial cells mitigates complement deposition: implications for macular degeneration
- Creators
- Kelly Mulfaul - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USANathaniel K Mullin - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USAJoseph C Giacalone - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USAAndrew P Voigt - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USAMelette DeVore - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USAEdwin M Stone - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USABudd A Tucker - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USARobert F Mullins - Institute for Vision Research, Department of Ophthalmology & Visual Sciences, University of Iowa, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of pathology, Vol.257(1), pp.29-38
- DOI
- 10.1002/path.5867
- PMID
- 35038170
- PMCID
- PMC9007903
- NLM abbreviation
- J Pathol
- eISSN
- 1096-9896
- Grant note
- DOI: 10.13039/100012201, name: Elmer and Sylvia Sramek Charitable Trust; DOI: 10.13039/501100000615, name: Fight for Sight UK, award: PD‐20005; DOI: 10.13039/100000002, name: National Institutes of Health, award: EY‐024605, EY‐025580
- Language
- English
- Date published
- 01/17/2022
- Academic Unit
- The University of Iowa Institute for Vision Research; Iowa Neuroscience Institute; John and Marcia Carver Nonprofit Genetic Testing Laboratory; Ophthalmology and Visual Sciences
- Record Identifier
- 9984210347902771
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