|
| Status |
Public on Jan 01, 2019 |
| Title |
iRhom2 Promotes Lupus Nephritis through ADAM17-Dependent TNF-α and EGFR Signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.
|
| |
|
| Overall design |
[1] Analysis of total kidney transcriptomes in Fcgr2b-/- mice, Rhbdf2-/- mice; Rhbdf2 -/- Fcgr2b-/- mice and the wildtype control. [2] Analysis of CD45+F4/80hiCD11b+Ly6G-Ly6C- kidney macrophages transcriptomes in Fcgr2b-/- mice, Rhbdf2-/- mice; Rhbdf2 -/- Fcgr2b-/- mice and the wildtype control.
|
| |
|
| Contributor(s) |
Qing X, Chinenov Y, Redecha P, Blobel CP, Salmon JE |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| NIH grant(s) |
| Grant ID |
Grant title |
Affiliation |
Name |
| R01 GM064750 |
iRhoms 1 and 2: Key regulators of ADAM17-dependent EGFR signaling |
HOSPITAL FOR SPECIAL SURGERY |
Carl Peter Blobel |
|
| |
| Submission date |
Dec 05, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Yurii Chinenov |
| Organization name |
Hospital for special surgery
|
| Department |
Research Division
|
| Lab |
HSS Genomics Center
|
| Street address |
535 E 71 str, Hospital for Special Surgery
|
| City |
New york |
| State/province |
New York |
| ZIP/Postal code |
11361 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (28)
|
|
| Relations |
| BioProject |
PRJNA421160 |
| SRA |
SRP126164 |
Less...
More...