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Abstract: PO1427

Deletion of Smad3 Worsens Lupus Nephritis by Promoting B Cell Activation

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Xu, Wenqian, Department of Nephrology, Center of Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
  • Li, Jinhong, Department of Nephrology, Center of Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
  • Huang, Xiao Ru, Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Szeto, Cheuk-Chun, Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
  • Chan, Tak Mao Daniel, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
  • Yu, Xueqing, Guangdong-Hong Kong Joint Laboratory for Immunity and Genetics of Chronic Kidney Disease, Guangdong Academy of Medical Science, Guangdong Provincial People’s Hospital, Guangzhou, China
  • Zheng, Zhihua, Department of Nephrology, Center of Urology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
  • Lan, Hui Y., Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, and Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
Background

TGF-β signaling has been shown to play a critical role in many autoimmune diseases. However, its regulatory role in lupus nephritis remains unknown, which was investigated in the present study in a mouse model of lupus nephritis (LN) in which Smad3 gene was deficient.

Methods

To investigate the role of Smad3 in LN, we generated Smad3 knockout (KO) lupus mice by cross-breeding Smad3+/- mouse with B6.NZMSle1-3 lupus mice (C57BL/6J background) mouse. We then determined the regulatory role of Smad3 in the pathogenesis of LN and investigated the regulatory mechanisms of Smad3 in T cell and B cell activation and autoantibody production in Smad3 KO LN and Smad3 WT LN mice and B cells in vivo and in vitro.

Results

We successfully deleted the Smad3 gene from B6.NZMSle1-3 mice with unexpected findings that Smad3KO-LN mice developed much more severe LN with higher mortality rate (50%), higher circulating anti-dsDNA (60%), higher levels of serum creatinine (Cr, 30%) but lower creatinine clearance rate (Ccr, 20%), more severe glomerular necrosis (50%), massive renal immune complex deposition and complement activation, and progressive renal inflammation and functional injury. Mechanistically, we observed that lupus mice lacking Smad3 largely promoted Th1, Th2 and Th17 populations while suppressed Treg immune responses in the kidney. Unexpectedly, deletion of Smad3 largely increased macrophage inducible lectin-receptor (Mincle) expression by B220+ B cells (80%). Further studies showed that B cells lacking Smad3 were largely promoted Cytosine-phosphorothioate-guanine oligodeoxynucleotides (CpG ODN)-induced but failed to response to the inhibitory effect of TGF-β1 on Mincle-Syk-NFκB signaling, MHC II and CD86 expression, and autoantibody production. Importantly, silencing Mincle inhibited CpG ODN-induced Syk-NFκB signaling and IgG production by splenic B cells.

Conclusion

TGF-β/Smad3 signaling plays a protective role in LN by maintaining the balance of T cell immunity and B cell function. Loss of Smad3 worsens LN by shifting Treg to Th1, Th2 and Th17 and promoting B cell activation and autoantibody production via the Mincle-Syk-NFκB-dependent mechanism. Thus, outcomes from this study will be of great significance both scientifically and clinically.

Funding

  • Government Support – Non-U.S.