Repeated administration of alpha-galactosylceramide ameliorates experimental lupus nephritis in mice

Takahiro Uchida,Seigo Ito,Shuhji Seki,Hiroyuki Nakashima,Takuya Ishikiriyama,Akira Yamagata,Naoki Oshima,Masahiro Nakashima,Hiroo Kumagai

doi:10.1038/s41598-018-26470-w

Takahiro Uchida, Seigo Ito + Show 7 more

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https://doi.org/10.1038/s41598-018-26470-w

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Journal: Scientific Reports	Publication Date: May 29, 2018
Citations: 17	License type: open-access

Affiliation: National Defense Medical College

Abstract

Lupus nephritis is a crucial complication of systemic lupus erythematosus. In this study, we investigated the roles of mouse natural killer T (NKT) cells in lupus nephritis. From 24 weeks of age, NZB/NZW F1 mice were injected with alpha-galactosylceramide (α-GalCer) or vehicle once a week for four weeks. In the α-GalCer group, the levels of proteinuria and blood urea nitrogen were significantly lower than those in the vehicle group. The histological evaluation showed a decrease in glomerular immune complex deposits and an alleviation of podocyte injury. The proportion of NKT cells in the mononuclear cell (MNC) fraction in the α-GalCer group was significantly decreased in the liver, kidney, and spleen. The proliferation and cytokine production in α-GalCer-stimulated liver MNCs were markedly diminished in the α-GalCer group (anergy). The IFN-γ production in liver MNCs stimulated by concanavalin A or an anti-CD3 antibody did not differ between the two groups, whereas the IL-4 production was significantly lower in the α-GalCer group. In addition, the IgM production in CpG-oligodeoxynucleotide-stimulated spleen MNCs was significantly lower in the α-GalCer group. These results suggest that α-GalCer suppressed Th2 immune responses in NKT cells and B cell function, thereby slowing the progression of lupus nephritis.

Highlights

Systemic lupus erythematosus (SLE) is one of the representative systemic autoimmune diseases, which is characterized by the presence of autoantibodies and involves virtually any organ
In a SLE model, the expansion of natural killer T (NKT) cells is thought to be involved in the onset of lupus nephritis[13], whereas their immunoregulatory roles were reported both in human SLE and SLE models[14,15,16]
We show that the repeated administration of α-GalCer into BWF1 mice induced beneficial effects, as follows: (i) it improved proteinuria which represents a hallmark of renal injury, by protecting nephrin, a key functional molecule in the slit diaphragm of the podocytes[21]; (ii) it suppressed B cell function and decreased glomerular immune complex deposits; (iii) it induced an anergic state to α-GalCer in NKT cells, and decreased the number of NKT cells in multiple organs and the production of IL-4 by these cells

Summary

Introduction

Systemic lupus erythematosus (SLE) is one of the representative systemic autoimmune diseases, which is characterized by the presence of autoantibodies and involves virtually any organ. Once activated by IL-12 or an anti-CD3 antibody (Ab), they produce cytokines and exert antitumor cytotoxicity[3,4] Their TCRs are mainly encoded by the Vα14Jα18 and Vβ8 genes[5,6]. In a SLE model, the expansion of NKT cells is thought to be involved in the onset of lupus nephritis[13], whereas their immunoregulatory roles were reported both in human SLE and SLE models[14,15,16]. There have been contradictory reports regarding the effects of α-GalCer in NZB/ NZW F1 (BWF1) mice, an experimental model of SLE in which lupus nephritis-like lesions develop. Showed that α-GalCer-activated NKT cells exacerbated the experimental lupus nephritis[19], whereas a long-term reduction in severe proteinuria following α-GalCer treatment was reported in another study[20]

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