CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway
Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifesty...
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| Format: | Article |
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/16/8727 |
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| author | Angela Armento Tiziana L. Schmidt Inga Sonntag David A. Merle Mohamed Ali Jarboui Ellen Kilger Simon J. Clark Marius Ueffing |
| author_facet | Angela Armento Tiziana L. Schmidt Inga Sonntag David A. Merle Mohamed Ali Jarboui Ellen Kilger Simon J. Clark Marius Ueffing |
| author_sort | Angela Armento |
| collection | DOAJ |
| description | Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (<i>CFH</i>), accounting for the majority of AMD risk. However, the exact mechanism of <i>CFH</i> dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous <i>CFH</i> locally in RPE cells, we silenced <i>CFH</i> in human hTERT-RPE1 cells. We demonstrate that endogenously expressed <i>CFH</i> in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., <i>C3, CFB</i> upregulation, and <i>C5</i> downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype. |
| first_indexed | 2024-03-10T08:44:58Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:44:58Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-96ad3800f3394486ac0f73b5f22636942023-11-22T07:59:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216872710.3390/ijms22168727CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB PathwayAngela Armento0Tiziana L. Schmidt1Inga Sonntag2David A. Merle3Mohamed Ali Jarboui4Ellen Kilger5Simon J. Clark6Marius Ueffing7Institute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Department for Ophthalmology, Eberhard Karls University of Tübingen, 72076 Tübingen, GermanyAge-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (<i>CFH</i>), accounting for the majority of AMD risk. However, the exact mechanism of <i>CFH</i> dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous <i>CFH</i> locally in RPE cells, we silenced <i>CFH</i> in human hTERT-RPE1 cells. We demonstrate that endogenously expressed <i>CFH</i> in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., <i>C3, CFB</i> upregulation, and <i>C5</i> downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.https://www.mdpi.com/1422-0067/22/16/8727age-related macular degeneration (AMD)retinal pigment epithelium (RPE) cellscomplement factor H (CFH)inflammationcytokinesNF-κB pathway |
| spellingShingle | Angela Armento Tiziana L. Schmidt Inga Sonntag David A. Merle Mohamed Ali Jarboui Ellen Kilger Simon J. Clark Marius Ueffing CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway International Journal of Molecular Sciences age-related macular degeneration (AMD) retinal pigment epithelium (RPE) cells complement factor H (CFH) inflammation cytokines NF-κB pathway |
| title | CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway |
| title_full | CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway |
| title_fullStr | CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway |
| title_full_unstemmed | CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway |
| title_short | CFH Loss in Human RPE Cells Leads to Inflammation and Complement System Dysregulation via the NF-κB Pathway |
| title_sort | cfh loss in human rpe cells leads to inflammation and complement system dysregulation via the nf κb pathway |
| topic | age-related macular degeneration (AMD) retinal pigment epithelium (RPE) cells complement factor H (CFH) inflammation cytokines NF-κB pathway |
| url | https://www.mdpi.com/1422-0067/22/16/8727 |
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