iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Xiaoping Qing, Yurii Chinenov, Patricia Redecha, Michael P. Madaio, Joris J.T.H. Roelofs, Gregory Farber, Priya D. Issuree, Laura Donlin, David R. Mcllwain, Tak W. Mak, Carl P. Blobel, Jane E. Salmon

Research output: Contribution to journalArticle

16 Citations (Scopus)

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-α 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-doublestranded DNA (anti-dsDNA) Ab production by simultaneously blocking HB-EGF/EGFR and 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 target for selective and simultaneous dual inhibition of 2 major pathological pathways in the effector arm of the disease.

Original languageEnglish (US)
Pages (from-to)1397-1412
Number of pages16
JournalJournal of Clinical Investigation
Volume128
Issue number4
DOIs
StatePublished - Apr 2 2018

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Lupus Nephritis
Kidney
Epidermal Growth Factor
Heparin
Disintegrins
Metalloproteases
Gene Expression Profiling
Chronic Renal Insufficiency
Macrophages
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Qing, X., Chinenov, Y., Redecha, P., Madaio, M. P., Roelofs, J. J. T. H., Farber, G., ... Salmon, J. E. (2018). iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. Journal of Clinical Investigation, 128(4), 1397-1412. https://doi.org/10.1172/JCI97650

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. / Qing, Xiaoping; Chinenov, Yurii; Redecha, Patricia; Madaio, Michael P.; Roelofs, Joris J.T.H.; Farber, Gregory; Issuree, Priya D.; Donlin, Laura; Mcllwain, David R.; Mak, Tak W.; Blobel, Carl P.; Salmon, Jane E.

In: Journal of Clinical Investigation, Vol. 128, No. 4, 02.04.2018, p. 1397-1412.

Research output: Contribution to journalArticle

Qing, X, Chinenov, Y, Redecha, P, Madaio, MP, Roelofs, JJTH, Farber, G, Issuree, PD, Donlin, L, Mcllwain, DR, Mak, TW, Blobel, CP & Salmon, JE 2018, 'iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling', Journal of Clinical Investigation, vol. 128, no. 4, pp. 1397-1412. https://doi.org/10.1172/JCI97650
Qing X, Chinenov Y, Redecha P, Madaio MP, Roelofs JJTH, Farber G et al. iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. Journal of Clinical Investigation. 2018 Apr 2;128(4):1397-1412. https://doi.org/10.1172/JCI97650
Qing, Xiaoping ; Chinenov, Yurii ; Redecha, Patricia ; Madaio, Michael P. ; Roelofs, Joris J.T.H. ; Farber, Gregory ; Issuree, Priya D. ; Donlin, Laura ; Mcllwain, David R. ; Mak, Tak W. ; Blobel, Carl P. ; Salmon, Jane E. / iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 4. pp. 1397-1412.
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