CpG oligodeoxynucleotides (ODNs), as a novel type of adjuvant with immunomodulatory effects, are recognized by Toll-like receptors (TLRs) in Litopenaeus vannamei. In the present study, eleven LvTLRs-pCMV recombinants (rLvTLRs) were constructed to investigate the relationships between various CpG ODNs and different LvTLRs in human embryonic kidney 293T (HEK293T) cells, which was further confirmed by bio-layer interferometry (BLI) technique. The results of dual luciferase reporter assay showed that every LvTLR could activate multiple downstream genes, mainly including NF-κB, CREB, ISRE, IL-6-promoter, TNF-α-promoter and Myc, thereby inducing main signaling pathways in shrimps. Most CpG ODNs possessed affinities to more than one LvTLR, while each LvTLR could recognize multiple CpG ODNs, and the widely recognized ligands within CpG ODNs are A-class and B-class. Moreover, BLI analysis showed that CpG 2216, Cpg 2006, CpG 2143 and CpG 21425 exhibited dose-dependent affinity to the expressed TLR protein, which were consistent with the results in HEK293T cells. It suggested that the interactions of CpG ODNs with LvTLRs were indispensable for the immune regulation triggered by CpG ODNs, and these findings would lay foundations for studying the activations of LvTLRs to immune signaling pathways and shedding lights on the immune functions and mechanisms of CpG ODNs.

10 Nov 2022·Mediators of Inflammation

ST3GAL3 Promotes the Inflammatory Response of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis by Activating the TLR9/MyD88 Pathway

Article

Author: Niu, Xuegang ; Xu, Liming ; Liu, Lining ; Liu, Yifan

This study is aimed at investigating the role of β-galactoside-α2,3-sialyltransferase III (ST3GAL3) in fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), as well as its potential mechanism of action. The Gene Expression Omnibus (GEO) database and gene set enrichment analysis (GSEA) were used to analyse the expression of ST3GAL3 and the enrichment signalling pathways associated with ST3GAL3 in RA. The effects of ST3GAL3 on tumour necrosis factor- (TNF-) α and interleukin- (IL-) 1β-treated MH7A cells were determined using methyl thiazolyl tetrazolium (MTT), transwell, and enzyme-linked immunosorbent assays (ELISA). The expression of proliferation-associated proteins and Toll-like receptor (TLR) pathway-enriched proteins was analysed using western blotting. As a main result, ST3GAL3 was screened as an overlapping upregulated gene from GSE101193 and GSE94519 datasets. ST3GAL3 expression in MH7A cells significantly increased with increasing treatment time with TNF-α or IL-1β. TLR9/myeloid differentiation primary response protein 88 (MyD88) is a downstream activation pathway of ST3GAL3. ST3GAL3 overexpression promoted MH7A cell proliferation and migration. Additionally, ST3GAL3 overexpression upregulated the expression of proliferation-associated proteins (cyclinD, cyclinE, and proliferating cell nuclear antigen) and TLR pathway enrichment factors (TLR9 and MyD88) and increased the production of matrix metallopeptidase (MMP) 1, MMP3, interleukin- (IL-) 6, and IL-8, whereas si-ST3GAL3 had the opposite effect. The addition of TLR9 agonists (CpG 2216 and CpG 2006) reversed the effects of si-ST3GAL3 on MH7A cell proliferation, migration, and inflammation. TLR9-specific siRNA reversed the effects of ST3GAL3 overexpression on MH7A cell proliferation, migration, and inflammation. In conclusion, ST3GAL3 is likely involved in RA pathogenesis by activating the TLR9/MyD88 pathway.

01 Jan 2017·Mediators of InflammationQ3 · MEDICINE

Increased Abundance of Plasmacytoid Dendritic Cells and Interferon-Alpha Induces Plasma Cell Differentiation in Patients of IgA Nephropathy

Q3 · MEDICINE

ArticleOA

Author: Wang, Bing ; Kong, Qingyu ; Zheng, Nuoyan ; Luo, Ning ; Ye, Hongjian ; Ming, Hongyan ; Yu, Xueqing ; Zhang, Jiqin ; Fan, Jinjin

The roles of pDC and IFN-αhave not been well defined in IgA nephropathy (IgAN). In this study, we investigated the abundance of pDCs and IFN-αin IgAN patients and the response of peripheral blood mononuclear cells (PBMCs) after stimulation of the pDC-preferred TLR9 ligand CpG2216. The effects of IFN-αon plasma cell differentiation and leukocyte migration were also investigated. Here, we found that the percentages of pDCs were increased in PBMCs of IgAN patients, than in those of healthy controls. Plasma levels of IFN-αproteins and abundance of plasma cells were higher in IgAN patients than in healthy donors. Plasma IFN-αlevels were positively associated with proteinuria, renal IgM deposition, and renal tubular atrophy/interstitial fibrosis grade in IgAN patients. Ex vivo activation of TLR9 on pDCs resulted in increased IFN-αproduction and enhanced plasma cell differentiation in IgAN patients as compared with healthy donors. IFN-αtreatment led to increased plasma cell differentiationin vitro. IFN-αalso significantly promoted expression of chemokines IP-10 and MCP-1 in human mesangial cells, which subsequently facilitated the transendothelial migration of human CD4+and CD14+cells. In conclusion, pDC and its secreted cytokine IFN-αmay play important roles in pathological changes of IgA nephropathy.

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