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| Status |
Public on Jan 20, 2023 |
| Title |
INFLAMMATION OF THE RETINAL PIGMENT EPITHELIUM DRIVES EARLY-ONSET PHOTORECEPTOR DEGENERATION IN MERTK-ASSOCIATED RETINITIS PIGMENTOSA |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation is determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation, even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk -/- mice. Neither inflammation nor severe, early-onset PR degeneration were observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function.
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| Overall design |
(C57BL/6, Tyro3-/-V1 and Mertk-/-V2Tyro3-/-V2 ) and (WT129 and Itgb5-/-) RPE were collected at post-natal day 25 (1 hour after light onset) and processed for RNA sequencing
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| Web link |
https://www.science.org/doi/10.1126/sciadv.ade9459
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| Contributor(s) |
Mercau ME, Akalu YT, Finnemann SC, Rothlin CV, Ghosh S |
| Citation(s) |
36662852 |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 CA212376 |
An innate immune checkpoint in cancer immunotherapy |
YALE UNIVERSITY |
Sourav Ghosh |
| R01 CA212376 |
An innate immune checkpoint in cancer immunotherapy |
YALE UNIVERSITY |
Carla Rothlin |
| R01 EY026215 |
Molecular mechanisms of outer segment renewal |
FORDHAM UNIVERSITY |
SILVIA C FINNEMANN |
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| Submission date |
Sep 23, 2022 |
| Last update date |
Feb 10, 2023 |
| Contact name |
Maria Elisa Mercau |
| E-mail(s) |
maria.mercau@yale.edu
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| Organization name |
Yale University
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| Department |
Immunobiology
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| Street address |
300 Cedar st
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| City |
New Haven |
| ZIP/Postal code |
06519 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (18)
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| GSM6597682 |
RPE, C57BL/6, P25, Biol rep 1 [B6J_23_1] |
| GSM6597683 |
RPE, C57BL/6, P25, Biol rep 2 [B6J_23_2] |
| GSM6597684 |
RPE, C57BL/6, P25, Biol rep 3 [B6J_23_3] |
| GSM6597685 |
RPE, C57BL/6, P25, Biol rep 4 [BL6J_7] |
| GSM6597686 |
RPE, C57BL/6, P25, Biol rep 5 [BL6J_8] |
| GSM6597687 |
RPE, C57BL/6, P25, Biol rep 6 [BL6J_9] |
| GSM6597688 |
RPE, Tyro3-/-V1, P25, Biol rep 1 [Tyro3_23_1] |
| GSM6597689 |
RPE, Tyro3-/-V1, P25, Biol rep 2 [Tyro3_23_2] |
| GSM6597690 |
RPE, Tyro3-/-V1, P25, Biol rep 3 [Tyro3_23_3] |
| GSM6597691 |
RPE,Mertk-/-V2Tyro3-/-V2, P25, Biol rep 1 [DKO_23_1] |
| GSM6597692 |
RPE,Mertk-/-V2Tyro3-/-V2, P25, Biol rep 2 [DKO_23_2] |
| GSM6597693 |
RPE,Mertk-/-V2Tyro3-/-V2, P25, Biol rep 3 [DKO_23_3] |
| GSM6597694 |
RPE, WT129, P25, Biol rep 1 [WT129_1] |
| GSM6597695 |
RPE, WT129, P25, Biol rep 2 [WT129_2] |
| GSM6597696 |
RPE, WT129, P25, Biol rep 3 [WT129_3] |
| GSM6597697 |
RPE, Itgb5-/-, P25, Biol rep 1 [Itgb5_1] |
| GSM6597698 |
RPE, Itgb5-/-, P25, Biol rep 2 [Itgb5_2] |
| GSM6597699 |
RPE, Itgb5-/-, P25, Biol rep 3 [Itgb5_3] |
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| Relations |
| BioProject |
PRJNA883604 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE214005_Normalized_Count_table_RPE_B6_Tyro3_DKO_only.xlsx |
6.6 Mb |
(ftp)(http) |
XLSX |
| GSE214005_Normalized_count_WT129_Itgb5_only.xlsx |
3.7 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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