IL-17B alleviates the pathogenesis of systemic lupus erythematosus by inhibiting FASN-mediated differentiation of B cells
Yucai Xiao, Yuxin Hu, Yangzhe Gao, Lin Wang, Lili Zhang, Qun Ma, Zhaochen Ning, Lu Yu, Haochen Li, Jiakun Liu, Junyu Wang, Yonghong Yang, Huabao Xiong, Guanjun Dong
Yucai Xiao, Yuxin Hu, Yangzhe Gao, Lin Wang, Lili Zhang, Qun Ma, Zhaochen Ning, Lu Yu, Haochen Li, Jiakun Liu, Junyu Wang, Yonghong Yang, Huabao Xiong, Guanjun Dong
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Research Article

IL-17B alleviates the pathogenesis of systemic lupus erythematosus by inhibiting FASN-mediated differentiation of B cells

Abstract

The interleukin 17 (IL-17) family of cytokines has emerged as a critical player in autoimmune disease, including systemic lupus erythematosus (SLE). However, the role of IL-17B, a poorly understood cytokine, in the pathogenesis of SLE is still not known. In this study, we investigated the role of IL-17B in the activation and differentiation of B cells, and the pathogenesis of SLE. Intriguingly, IL-17B deficiency aggravated disease in lupus-prone mice and promoted the activation of B cells and the differentiation of germinal center B cells and plasma cells, while recombinant mouse IL-17B (rmIL-17B) significantly alleviated disease in lupus-prone mice. Mechanistically, rmIL-17B inhibited the activation of the Toll-like receptor and interferon pathways in B cells by downregulating fatty acid synthase–mediated (FASN-mediated) lipid metabolism. Loss of FASN significantly alleviated the disease in lupus-prone mice and inhibited the activation and differentiation of B cells. In addition, B cells had greater FASN expression and lower IL-17RB levels in patients with SLE than in healthy controls. Our study describes the role of IL-17B in regulating B cell activation and differentiation, and alleviating the onset of SLE. These findings will lay a theoretical foundation for further understanding of the pathogenesis of SLE.

Authors

Yucai Xiao, Yuxin Hu, Yangzhe Gao, Lin Wang, Lili Zhang, Qun Ma, Zhaochen Ning, Lu Yu, Haochen Li, Jiakun Liu, Junyu Wang, Yonghong Yang, Huabao Xiong, Guanjun Dong

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Figure 4

IL-17B suppresses the activation of B cells by attenuating the FASN/OXPHOS/ATP axis.

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IL-17B suppresses the activation of B cells by attenuating the FASN/OXPH...
(A) PCA plot, (B) volcano plot, and (C) KEGG analysis of metabolites generated from serum lipid profiles of IMQ-treated WT (n = 6) and IL-17B–KO mice (n = 6). (D) The FASN intensity on each cell from IMQ-treated WT mice (n = 2) and IL-17B–KO mice (n = 2) was expressed as z score–normalized expression. Dashed-line circles indicate GC B cells. (E and F) Western blot and flow cytometry analysis of FASN expression in B cells after different time periods of rmIL-17B treatment. (G) Quantitative PCR analysis was performed to assess the expression of FASN in B cells following treatment with varying concentrations of rmIL-17B. (H–M) B cells, isolated from the spleen of WT mice or FASN+/– mice, were stimulated with LPS, R848, and CpG-1826. Expression of (H) CD40, (I) CD69, and (J) CD86 at 24 hours. mRNA levels of (K) IL-12 and (L) TNF-α at 6 hours. (M) Phosphorylation of p65, p38, JNK, and Erk. (N–S) B cells, isolated from the spleen of WT mice or FASN+/– mice, were stimulated with IFN-α. (N) CD40, (O) CD69, and (P) CD86 expression at 24 hours. (Q) MX1, (R) OAS1, and (S) IFIT1 mRNA levels at 6 hours. (T–V) B cells, isolated from the spleen of WT mice or FASN+/– mice, were stimulated with R848, and the (T and U) OCR was detected by seahorse, and the (V) ATP concentration was detected by ELISA. Murine splenic B cells were pretreated with rmIL-17B for 12 hours and stimulated with R848, and (W and X) OCR was detected. The data are shown as the mean ± SEM and are representative of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 by 1-way ANOVA with Tukey’s multiple-comparison test (F and G) or 2-tailed Student’s t test (H–L, N–S, U, V, and X). NS, P > 0.05.