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II-16 Protection of lupus nephritis by IRHOM2 deficiency in FCRγIIB-/- mice
  1. Xiaoping Qing1,
  2. Yuri Chinenov1,
  3. Michael Madaio2,
  4. Patricia Redecha1,
  5. Priya D Issuree3,
  6. David McIlwain4,
  7. Tak W Mak5,
  8. Carl P Blobel6 and
  9. Jane E Salmon1,7
  1. 1Program in Inflammation and Autoimmunity, Hospital for Special Surgery, USA
  2. 2Department of Medicine, Medical College of Georgia at Augusta University, USA
  3. 3Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, USA
  4. 4Department of Microbiology and Immunology, Stanford University, USA
  5. 5Princess Margaret Cancer Centre, University Health Network, Canada
  6. 6Department of Medicine, Department of Physiology, Systems Biology and Biophysics, Weill Medical College of Cornell University, USA
  7. 7Department of Medicine, Weill Medical College of Cornell University, USA


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.

Abstract II16 Figure 1

iRhom2 deficiency protects FcγRIIB-/- mice from developing severe kidney injury. FcγRIIB-/- mice crossed with iRhom2-/- mice were assessed for survival and kidney injury. Survival (A) and proteinuria (B) were plotted at each age. Pathological scores were illustrated for glomerular (C) and tubular-interstitial area (D) respectively. (A) survival, Chi square test. (B) proteinuria, student t-test. (C, D) pathological scores, non-parametric Mann Whitney test. ** P < 0.005, **** P < 0.0001

Acknowledgements Work supported by Lupus Research Institute (JES and CB) and Barbara Volcker Centre of Hospital for Special Surgery (XQ).

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