Abstract
Objective
Triggering receptors expressed on myeloid cells-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits by targeting TREM-1 remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). Disorders of epigenetic processes including non-coding RNAs give rise to SLE, resulting in complicated syndromes. Here, we aim to address this issue and explore the miRNA to inhibit the activation of mDCs and alleviate the progress of SLE by targeting TREM-1 signal axis.
Methods
Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between patients with SLE and healthy individuals by four mRNA microarray datasets from Gene Expression Omnibus (GEO). Then we identified the expression of TREM-1 and its soluble form (sTREM-1) in clinical samples by ELISA, quantitative real-time PCR and Western blot. Phenotypic and functional changes of mDCs elicited by TREM-1 agonist were determined. Three databases of miRNAs target prediction and a dual-luciferase reporter assay were used to screen and verify miRNAs that can directly inhibit TREM-1 expression in vitro. Moreover, pristane-induced lupus mice were injected with miR-150-5p agomir to evaluate the effects of miR-150-5p on mDCs in lymphatic organs and disease activity in vivo.
Results
We screened TREM-1 as one of the hub genes closely correlated with the progression of SLE and identified sTREM-1 in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promoted activation and chemotaxis of mDCs and increased the production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α, and MCP-1. We showed that lupus mice displayed a unique miRNA signature in spleen, among which miR-150 was the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppressed the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicated that administration of miR-150-5p agomir effectively ameliorated lupus symptoms. Intriguingly, miR-150 inhibited the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues.
Conclusions
TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.
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Data availability
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- SLE:
-
Systemic lupus erythematosus
- miRNAs:
-
MicroRNAs
- WT:
-
Wild type
- HE:
-
Hematoxylin–eosin
- IF:
-
Immunofluorescence
- RT-PCR:
-
Quantitative real-time reverse transcription-polymerase chain reaction
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- DEGs:
-
Differentially expressed genes
- PBMC:
-
Peripheral blood mononuclear cell
- C3:
-
Complement 3
- Ig:
-
Immunoglobulin
- HC:
-
Healthy control
- NC:
-
Negative control
- SLEDAI:
-
Systemic lupus erythematosus disease activity index
- ROC:
-
Receiver operating characteristic
- AUC:
-
Area under the ROC curve
- ELISA:
-
Enzyme-linked immunosorbent assay
- WB:
-
Western blot
- PAS:
-
Periodic acid-Schiff
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Funding
This study was supported by National Natural Science Foundation of China (grant no. 81901660), Science and Technology Plan Project of Wenzhou (grant nos. Y20220389, Y20220045), and Zhejiang Province Natural Science Foundation (grant no. LTGY23H100001).
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CH conceived the project. CH and CY designed the experiments. CY collected and assembled data with help from WW, SG, JY, TZ, ZX, YX, HQ, XZ, SL and AY. CH and CY prepared the first draft of the manuscript. LW, JW and CH supervised the work. All authors reviewed and approved the manuscript.
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Informed consent was obtained from all human participants. All experiments were carried out in accordance with guidelines from the research committee at Wenzhou Medical University (Certificate No. SYXK- (Zhejiang, China) (2018–0017)). The study protocol was approved by the Clinical Research Ethics Committees of the First Affiliated Hospital of Wenzhou Medical University.
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Yue, C., Wang, W., Gao, S. et al. Agomir miRNA-150-5p alleviates pristane-induced lupus by suppressing myeloid dendritic cells activation and inflammation via TREM-1 axis. Inflamm. Res. 72, 1391–1408 (2023). https://doi.org/10.1007/s00011-023-01754-8
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DOI: https://doi.org/10.1007/s00011-023-01754-8