iRhom2 promotes lupus nephritis through TNF-<strong>α</strong> and EGFR signaling

Xiaoping Qing

Yurii Chinenov

Patricia Redecha

Michael Madaio

David Mcllwain+3 authors

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^{Program in Inflammation and Autoimmunity, and}

^{Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA.}

^{Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.}

^{Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.}

^{Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, New York, USA.}

^{Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, California, USA.}

^{Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.}

^{Institute for Advanced Study, Technical University Munich, Munich, Germany.}

^{Department of Medicine, Weill Cornell Medicine, New York, New York, USA.}

^{Corresponding author.}

Address correspondence to: Jane E. Salmon, Inflammation and Autoimmunity Program, S-Building, Room 701, Hospital for Special Surgery, 515 East 71st Street, New York, New York 10021, USA. Phone: 212.606.1422; Email: ude.ssh@jnomlas.

Xiaoping Qing: ude.ssh@xgniq; Yurii Chinenov: ude.ssh@yvonenihc; Patricia Redecha: moc.liamtoH@ahcedeR_T; Michael Madaio: ude.atsugua@OIADAMM; Joris J.T.H. Roelofs: ln.avu.cma@sfoleor.j.j; Gregory Farber: ude.llenroc.dem@5002frg; Priya D. Issuree: moc.liamg@eerussi.ayirp; Laura Donlin: UDE.SSH@LnilnoD; Tak W. Mak: ac.otnorotu.sernhu@kamt; Carl P. Blobel: ude.ssh@clebolb; Jane E. Salmon: ude.ssh@jnomlasAddress correspondence to: Jane E. Salmon, Inflammation and Autoimmunity Program, S-Building, Room 701, Hospital for Special Surgery, 515 East 71st Street, New York, New York 10021, USA. Phone: 212.606.1422; Email: ude.ssh@jnomlas.

Received 2017 Oct 11; Accepted 2018 Jan 23.

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-double-stranded 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.

Keywords: Autoimmunity, Inflammation

Keywords: Lupus, Mouse models

Abstract

Acknowledgments

This work is supported by the Lupus Research Institute (to JES and CPB), NIH grant GM64750 (to CPB), and the Michael D. Lockshin Fellowship of the Barbara Volcker Center for Women and Rheumatic Disease at the Hospital for Special Surgery (to XQ). We thank Gang Lin (Weill Cornell Medical College), Frank Barrat (Hospital for Special Surgery), and Nike Claessen and Onno J. de Boer (Department of Pathology, Academic Medical Center, University of Amsterdam) for thoughtful suggestions and technical support for the project and Amgen Inc. for providing murine p75TNFR:Fc.

Acknowledgments

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Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2018;128(4):1397–1412.https://doi.org/10.1172/JCI97650.

Footnotes

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