iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling
Xiaoping Qing, … , Carl P. Blobel, Jane E. Salmon
Xiaoping Qing, … , Carl P. Blobel, Jane E. Salmon
Published January 25, 2018
Citation Information: J Clin Invest. 2018;128(4):1397-1412. https://doi.org/10.1172/JCI97650.
View: Text | PDF
Research Article Autoimmunity Inflammation

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

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.

Authors

Xiaoping Qing, Yurii Chinenov, Patricia Redecha, Michael 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

×

Figure 3

Deficiency of iRhom2 attenuated inflammatory cell infiltration without affecting renal deposition of IC and C3 in the kidneys of Fcgr2b–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Deficiency of iRhom2 attenuated inflammatory cell infiltration without a...
(A) Kidneys were stained for mIgG and C3 by immunofluorescence. Photographs shown represent kidneys from n = 4 WT, n = 4 Rhbdf2–/–, n = 10 Fcgr2b–/–, and n = 10 Fcgr2b–/–Rhbdf2–/– mice. Scale bar: 25 μm. (B–F) Inflammatory cell infiltrates were analyzed by flow cytometry in mouse kidneys. Cell numbers of CD45+ leukocytes (B), macrophages (C), neutrophils (D), Ly6Chi monocytes, (E) and T cell subsets (F) are illustrated. Numbers shown are cells per kidney. (B–E) n = 8 WT, n = 5 Rhbdf2–/–, 8 Fcgr2b–/–, n = 8 Fcgr2b–/–Rhbdf2–/– mice. (F) n = 10 Fcgr2b–/–, n = 9 Fcgr2b–/–Rhbd2–/– mice. Data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 1-way ANOVA with Dunnett’s multiple comparisons test (A–E), 2-tailed unpaired Student’s t test (F).