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Longdan Xiegan Decoction alleviates experimental autoimmune uveitis in rats by inhibiting Notch signaling pathway activation and Th17 cell differentiation - 19/02/21

Doi : 10.1016/j.biopha.2021.111291 
Xuewei Yin a, 1, Yan Qiu b, 1, Zonghong Li a, 1, Lijie Guo c, Huixia Wei a, Bin Liu d, Mengxian Zhou a, Tuling Li a, Lihan Wang e, Wenjun Jiang e, Hongsheng Bi e, Dadong Guo a, e,
a Shandong University of Traditional Chinese Medicine, Jinan, 250002, China 
b The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250002, China 
c School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China 
d Department of Blood Transfusion, Linyi People's Hospital, No. 27#, Jiefang Road, Linyi, 276005, China 
e Shandong Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Therapy of Ocular Diseases, Eye Institute of Shandong University of Traditional Chinese Medicine, Jinan, 250002, China 

Corresponding author at: Eye Institute of Shandong University of Traditional Chinese Medicine, No. 48#, Yingxiongshan Road, Jinan, 250002, China.Eye Institute of Shandong University of Traditional Chinese MedicineNo. 48#Yingxiongshan RoadJinan250002China

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Highlights

The pathogenesis of uveitis is associated with the activation of Notch signaling.
A disturbed CD4+/CD8+, Th17/Treg balance occurs in EAU rats.
LXD can efficiently inhibit the activation of the Notch signaling pathway.
LXD can suppress Th17 cell differentiation and inflammatory cytokine expression.
LXD can restore the CD4+/CD8+, Th17/Treg balance.

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Abstract

This study aimed to investigate the dynamic effects of the traditional Chinese medicine compound Longdan Xiegan Decoction (LXD) on the inhibition of Notch signaling pathway activation and T helper (Th) cell differentiation in rats with experimental autoimmune uveitis (EAU). Based on a network pharmacology strategy, we conducted protein interaction network analysis to construct an active ingredient-disease treatment network. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were further used to screen out the possible signaling pathways regulated by LXD in the treatment of uveitis. In the subsequent functional studies, we established an EAU rat model and investigated the regulatory role of LXD in the Notch signaling pathway and Th cell differentiation in rats with EAU. Female Lewis rats were randomly divided into a normal control (NC) group, an EAU group, and an LXD group. After the induction of EAU, the ocular inflammation and pathological changes in the rats in each group were observed; for documentation, a scanning laser ophthalmoscope (SLO) was used to observe fundus inflammation on day 12 after immunization. Additionally, quantitative polymerase chain reaction (Q-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of Notch1, DLL4, IL-10 and IL-17A in the spleen, lymph nodes and ocular tissues of each group at 0, 6, 9, 12, 15 and 18 days after immunization. In addition, the dynamic frequencies of the CD4+, CD8+, Th17 and Treg cell subsets in the spleen, lymph nodes and ocular tissues were measured by flow cytometry. We found that the Notch signaling pathway was activated and the Th17 frequency was elevated in rats with EAU, leading to disrupted CD4+/CD8+ and Th17/Treg balance. The expression of Notch1, DLL4 and IL-17 mRNA and proteins in the EAU and LXD groups reached a peak on day 12, and then gradually decreased (all P < 0.05), and the ratios of the CD4+/CD8+ and Th17/Treg also peaked on day 12. However, after treatment with LXD, the expression of Notch1, DLL4 and IL-17 mRNA and proteins was significantly decreased (all P < 0.05), and the CD4+/CD8+ and Th17/Treg ratios significantly gradually returns to balance. LXD can efficiently inhibit Th17 cell differentiation, decrease inflammatory cytokine expression, and restore the CD4+/CD8+ and Th17/Treg balance by inhibiting the activation of the Notch signaling pathway in rats with EAU, thus effectively alleviating eye inflammation, protecting eye tissue structures, and positively regulating the immune state of the whole body and the intraocular microenvironment.

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Keywords : Experimental autoimmune uveitis, Longdan Xiegan Decoction, Network pharmacology, Notch signaling pathway, CD4+/CD8+, Th17/Treg


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© 2021  The Authors. Publicado por Elsevier Masson SAS. Todos los derechos reservados.
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Vol 136

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