II-16 Protection of lupus nephritis by IRHOM2 deficiency in FCRγIIB-/- mice. (31st August 2016)

• Record Type: Journal Article
• Authors: Qing, Xiaoping; Chinenov, Yuri; Madaio, Michael; Redecha, Patricia; Issuree, Priya D; McIlwain, David; Mak, Tak W; Blobel, Carl P; Salmon, Jane E
• Is Part Of: Lupus science & medicine. Volume 3(2016)Supplement 1
• Page Start: A23
• Page End: A24
• Publication Date: 2016-08-31
• Subjects: Systemic lupus erythematosus -- Periodicals; 616.772005
• DOI: 10.1136/lupus-2016-000179.46
• Languages: English
• ISSNs: 2398-8851

Abstract

Abstract : Background: Lupus nephritis (LN) is a major cause of morbidity and mortality in lupus. A disintegrin and metalloprotease 17 (ADAM17), is a principal membrane-anchored metalloprotease that cleaves a large spectrum of membrane-bound proteins into their soluble forms. Inactive rhomboid protein 2 (iRhom2), a newly identified regulator of ADAM17, controls maturation and function of ADAM17. Interestingly, in iRhom2 − /− mice, loss of ADAM17-dependent shedding activity is limited to the immune organs. Accumulating evidence has shown increased protein shedding and possibly activation of ADAM17 in lupus. Among ADAM17 substrates, tumour necrosis factor α (TNF-α) and heparin-binding EGF (HB-EGF) have been reported to play important roles in mediating renal damage in lupus. We hypothesised that the activation of iRhom2/ADAM17 pathway plays a role in the pathogenesis of lupus nephritis. Materials and methods: We crossed iRhom2 − /− mice with the well-established FcRγIIB-/- lupus-prone mice, and assessed development of lupus-like syndrome in these mice. Results: We found that iRhom2 deficiency protects FcRγIIB − /− mice from severe kidney damage (Figure 1 ), with minimal impact on the production of anti-double stranded (ds) DNA antibodies and renal deposition of immune complex and complement C3. In the absence of iRhom2, glomerular and tubule-interstitial structures were preserved, and massive inflammatory infiltrates including myeloid and CD4 + T cells were alleviated in the lupus kidneys. Protection of kidney injury by iRhom2 deficiency is associated with reduced EGFR signalling and ERK1/2 activation in the kidneys of FcRγIIB − /− mice. Transcriptome analysis of the whole kidneys as well as kidney macrophages from FcRγIIB − /− mice identified genes encoding pro-inflammatory cytokine/chemokines, fibrosis and tissue remodelling highly upregulated, and many of these genes were significantly reduced in the absence of iRhom2 . In addition, kidney biopsies from patients with lupus nephritis show intense staining for HB-EGF, an EGFR ligand, in areas of crescents. Conclusions: Our findings here provide the first evidence that iRhom2, a major regulator of ADAM17, plays a critical role in the pathogenesis of LN. The role of iRhom2 in a spontaneous chronic mouse model of LN, FcRγIIB − /− mice, appears to be targeting at the effector arm of the disease, rather than affecting the process of autoimmunity development. iRhom2 may be a potential therapeutic target in LN. Acknowledgements: Work supported by Lupus Research Institute (JES and CB) and Barbara Volcker Centre of Hospital for Special Surgery (XQ).