CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis
Cub domain-containing protein 1 (CDCP1) is a protein that is highly expressed on the surface of many cancer cells. However, its distribution in normal tissues and its potential roles in nontumor cells are poorly understood. We found that CDCP1 is present on both human and mouse retinal pigment epith...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-12-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.157038 |
| _version_ | 1797634402030714880 |
|---|---|
| author | Lingjun Zhang Nozha Borjini Yu Lun Sweta Parab Gospel Asonye Rupesh Singh Brent A. Bell Vera L. Bonilha Andrei Ivanov David A. Fox Rachel R. Caspi Feng Lin |
| author_facet | Lingjun Zhang Nozha Borjini Yu Lun Sweta Parab Gospel Asonye Rupesh Singh Brent A. Bell Vera L. Bonilha Andrei Ivanov David A. Fox Rachel R. Caspi Feng Lin |
| author_sort | Lingjun Zhang |
| collection | DOAJ |
| description | Cub domain-containing protein 1 (CDCP1) is a protein that is highly expressed on the surface of many cancer cells. However, its distribution in normal tissues and its potential roles in nontumor cells are poorly understood. We found that CDCP1 is present on both human and mouse retinal pigment epithelial (RPE) cells. CDCP1-KO mice developed attenuated retinal inflammation in a passive model of autoimmune uveitis, with disrupted tight junctions and infiltrating T cells detected in RPE flat mounts from WT but not CDCP1-KO mice during EAU development. Mechanistically, we discovered that CDCP1 on RPE cells was upregulated by IFN-γ in vitro and after EAU induction in vivo. CD6 stimulation induced increased RPE barrier permeability of WT but not CDCP1-knockdown (CDCP1-KD) RPE cells, and activated T cells migrated through WT RPE monolayers more efficiently than the CDCP1-KD RPE monolayers. In addition, CD6 stimulation of WT but not the CDCP1-KD RPE cells induced massive stress fiber formation and focal adhesion disruption to reduce cell barrier tight junctions. These data suggest that CDCP1 on RPE cells interacts with CD6 on T cells to induce RPE cytoskeleton remodeling and focal adhesion disruption, which open up the tight junctions to facilitate T cell infiltration for the development of uveitis. |
| first_indexed | 2024-03-11T12:08:19Z |
| format | Article |
| id | doaj.art-f158c9a10c174265a358b644e3a939a7 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:19Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-f158c9a10c174265a358b644e3a939a72023-11-07T16:24:36ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-12-01718CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitisLingjun ZhangNozha BorjiniYu LunSweta ParabGospel AsonyeRupesh SinghBrent A. BellVera L. BonilhaAndrei IvanovDavid A. FoxRachel R. CaspiFeng LinCub domain-containing protein 1 (CDCP1) is a protein that is highly expressed on the surface of many cancer cells. However, its distribution in normal tissues and its potential roles in nontumor cells are poorly understood. We found that CDCP1 is present on both human and mouse retinal pigment epithelial (RPE) cells. CDCP1-KO mice developed attenuated retinal inflammation in a passive model of autoimmune uveitis, with disrupted tight junctions and infiltrating T cells detected in RPE flat mounts from WT but not CDCP1-KO mice during EAU development. Mechanistically, we discovered that CDCP1 on RPE cells was upregulated by IFN-γ in vitro and after EAU induction in vivo. CD6 stimulation induced increased RPE barrier permeability of WT but not CDCP1-knockdown (CDCP1-KD) RPE cells, and activated T cells migrated through WT RPE monolayers more efficiently than the CDCP1-KD RPE monolayers. In addition, CD6 stimulation of WT but not the CDCP1-KD RPE cells induced massive stress fiber formation and focal adhesion disruption to reduce cell barrier tight junctions. These data suggest that CDCP1 on RPE cells interacts with CD6 on T cells to induce RPE cytoskeleton remodeling and focal adhesion disruption, which open up the tight junctions to facilitate T cell infiltration for the development of uveitis.https://doi.org/10.1172/jci.insight.157038Autoimmunity |
| spellingShingle | Lingjun Zhang Nozha Borjini Yu Lun Sweta Parab Gospel Asonye Rupesh Singh Brent A. Bell Vera L. Bonilha Andrei Ivanov David A. Fox Rachel R. Caspi Feng Lin CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis JCI Insight Autoimmunity |
| title | CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis |
| title_full | CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis |
| title_fullStr | CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis |
| title_full_unstemmed | CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis |
| title_short | CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis |
| title_sort | cdcp1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis |
| topic | Autoimmunity |
| url | https://doi.org/10.1172/jci.insight.157038 |
| work_keys_str_mv | AT lingjunzhang cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT nozhaborjini cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT yulun cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT swetaparab cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT gospelasonye cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT rupeshsingh cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT brentabell cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT veralbonilha cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT andreiivanov cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT davidafox cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT rachelrcaspi cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis AT fenglin cdcp1regulatesretinalpigmentedepithelialbarrierintegrityforthedevelopmentofexperimentalautoimmuneuveitis |