Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization
NLRP3 inflammasome activation and complement-mediated inflammation have been implicated in promoting choroidal neovascularization (CNV) in age-related macular degeneration (AMD), but central questions regarding their contributions to AMD pathogenesis remain unanswered. Key open questions are (1) whe...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/60194 |
| _version_ | 1818023844839948288 |
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| author | Jakob Malsy Andrea C Alvarado Joseph O Lamontagne Karin Strittmatter Alexander G Marneros |
| author_facet | Jakob Malsy Andrea C Alvarado Joseph O Lamontagne Karin Strittmatter Alexander G Marneros |
| author_sort | Jakob Malsy |
| collection | DOAJ |
| description | NLRP3 inflammasome activation and complement-mediated inflammation have been implicated in promoting choroidal neovascularization (CNV) in age-related macular degeneration (AMD), but central questions regarding their contributions to AMD pathogenesis remain unanswered. Key open questions are (1) whether NLRP3 inflammasome activation mainly in retinal pigment epithelium (RPE) or rather in non-RPE cells promotes CNV, (2) whether inflammasome activation in CNV occurs via NLRP3 or also through NLRP3-independent mechanisms, and (3) whether complement activation induces inflammasome activation in CNV. Here we show in a neovascular AMD mouse model that NLRP3 inflammasome activation in non-RPE cells but not in RPE cells promotes CNV. We demonstrate that both NLRP3-dependent and NLRP3-independent inflammasome activation mechanisms induce CNV. Finally, we find that complement and inflammasomes promote CNV through independent mechanisms. Our findings uncover an unexpected role of non-NLRP3 inflammasomes for CNV and suggest that combination therapies targeting inflammasomes and complement may offer synergistic benefits to inhibit CNV. |
| first_indexed | 2024-12-10T03:50:47Z |
| format | Article |
| id | doaj.art-e99e330bb6c54b80a21d14269dc1b98b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T03:50:47Z |
| publishDate | 2020-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e99e330bb6c54b80a21d14269dc1b98b2022-12-22T02:03:16ZengeLife Sciences Publications LtdeLife2050-084X2020-12-01910.7554/eLife.60194Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularizationJakob Malsy0Andrea C Alvarado1Joseph O Lamontagne2Karin Strittmatter3Alexander G Marneros4https://orcid.org/0000-0003-3866-020XCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United States; Department of Ophthalmology, University of Halle, Halle, GermanyCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United StatesCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United StatesCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United StatesCutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, United StatesNLRP3 inflammasome activation and complement-mediated inflammation have been implicated in promoting choroidal neovascularization (CNV) in age-related macular degeneration (AMD), but central questions regarding their contributions to AMD pathogenesis remain unanswered. Key open questions are (1) whether NLRP3 inflammasome activation mainly in retinal pigment epithelium (RPE) or rather in non-RPE cells promotes CNV, (2) whether inflammasome activation in CNV occurs via NLRP3 or also through NLRP3-independent mechanisms, and (3) whether complement activation induces inflammasome activation in CNV. Here we show in a neovascular AMD mouse model that NLRP3 inflammasome activation in non-RPE cells but not in RPE cells promotes CNV. We demonstrate that both NLRP3-dependent and NLRP3-independent inflammasome activation mechanisms induce CNV. Finally, we find that complement and inflammasomes promote CNV through independent mechanisms. Our findings uncover an unexpected role of non-NLRP3 inflammasomes for CNV and suggest that combination therapies targeting inflammasomes and complement may offer synergistic benefits to inhibit CNV.https://elifesciences.org/articles/60194inflammasomechoroidal neovascularizationneovascular age-related macular degenerationcomplementNLRP3caspase-1 |
| spellingShingle | Jakob Malsy Andrea C Alvarado Joseph O Lamontagne Karin Strittmatter Alexander G Marneros Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization eLife inflammasome choroidal neovascularization neovascular age-related macular degeneration complement NLRP3 caspase-1 |
| title | Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization |
| title_full | Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization |
| title_fullStr | Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization |
| title_full_unstemmed | Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization |
| title_short | Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization |
| title_sort | distinct effects of complement and of nlrp3 and non nlrp3 inflammasomes for choroidal neovascularization |
| topic | inflammasome choroidal neovascularization neovascular age-related macular degeneration complement NLRP3 caspase-1 |
| url | https://elifesciences.org/articles/60194 |
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