(5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fcγ receptor signaling

Authors: Qing QI1,2, Heng LI2,3, Ze-min LIN1,2, Xiao-qian YANG2, Feng-hua ZHU2, Yu-ting LIU2,3, Mei-juan SHAO1,2, Lu-yao ZHANG2,3, Yan-sheng XU1,2, Yu-xi YAN2,3, Lan-lan SUN2,4, Shi-jun HE2, Wei TANG2,3, Jian-ping ZUO1,2,3
1 Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2 Laboratory of Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
4 College of Chemical and Biomedical Engineering, University of Yichun, Yichun 336000, China
Corresponding to: Shi-jun HE:, Wei TANG:, Jian-ping ZUO:,
DOI: 10.1038/aps.2017.88
Received: 27 March 2017
Accepted: 17 June 2017
Advance online: 7 September 2017


(5R)-5-hydroxytriptolide (LLDT-8) is a novel triptolide analog that has been identified as a promising candidate for treating autoimmune diseases and has been shown to be effective in treating murine collagen-induced arthritis and lupus nephritis. In the present study, we investigated the therapeutic effect and possible mechanism of action of LLDT-8 in a murine anti-glomerular basement membrane (GBM) glomerulonephritis model. NZW mice were injected with rabbit anti-GBM serum (500 μL, ip). The mice were orally treated with LLDT-8 (0.125 mg/kg, every other day) or a positive control prednisolone (2 mg/kg every day) for 14 d. Blood and urine samples as well as spleen and kidney tissues were collected for analyses. LLDT-8 treatment did not affect the generation of mouse anti-rabbit antibodies. LLDT-8 significantly reversed established proteinuria, improved renal histopathology and attenuated renal dysfunction in glomerulonephritis mice. Furthermore, LLDT-8 inhibited inflammation in the kidney evidenced by significantly decreasing C3 and IgG deposition, reducing the levels of the pathogenic cytokines TNF-α, IL-6, IL-17, and IFN-γ, and reducing related chemokine expression and leukocyte infiltration in kidneys. Moreover, LLDT-8 treatment significantly increased the expression of FcγRIIB in the kidney and spleen. In addition, the treatment restored the reduced expression of FcγRIIB on the surface of kidney effector cells, CD11b+ cells, and interfered with FcγR-dependent signaling, especially FcγRIIB-mediated downstream kinases, such as BTK. These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fcγ receptor signaling.
Keywords: triptolide; (5R)-5-hydroxytriptolide (LLDT-8); prednisolone; glomerulonephritis; immune complexes; inflammation; Fcγ receptor signaling