Journal article
iRhom2 promotes lupus nephritis through TNF-alpha and EGFR signaling
The Journal of clinical investigation, Vol.128(4), pp.1397-1412
04/02/2018
DOI: 10.1172/JCI97650
PMCID: PMC5873859
PMID: 29369823
Abstract
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-alpha and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney diseases. Here, we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b(-/-) mice from developing severe kidney damage without altering anti-double stranded DNA (anti-dsDNA) Ab production by simultaneously blocking HB-EGF/EGFR and INF-alpha signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-alpha and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgab(-/-) mice, alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-alpha or EGFR signaling protected Frgr2(b-/-) 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-alpha and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a target for selective and simultaneous dual inhibition of 2 major pathological pathways in the effector arm of the disease.
Details
- Title: Subtitle
- iRhom2 promotes lupus nephritis through TNF-alpha and EGFR signaling
- Creators
- Xiaoping Qing - Program in Inflammation and Autoimmunity, and.Yurii Chinenov - Hospital for Special SurgeryPatricia Redecha - Program in Inflammation and Autoimmunity, and.Michael Madaio - Augusta UniversityJoris J. T. H. Roelofs - University of AmsterdamGregory Farber - Cornell UniversityPriya D. Issuree - Hospital for Special SurgeryLaura Donlin - Hospital for Special SurgeryDavid R. Mcllwain - Stanford UniversityTak W. Mak - Princess Margaret Cancer CentreCarl P. Blobel - Hospital for Special SurgeryJane E. Salmon - Weill Cornell Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.128(4), pp.1397-1412
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI97650
- PMID
- 29369823
- PMCID
- PMC5873859
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 16
- Grant note
- Barbara Volcker Center for Women and Rheumatic Disease at the Hospital for Special Surgery GM64750 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Lupus Research Institute R01GM064750 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 04/02/2018
- Academic Unit
- Infectious Diseases; Internal Medicine
- Record Identifier
- 9984359798502771
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