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The Role of miR-30d-5p in Neutrophil-Derived Exosomes in Promoting Systemic Lupus Erythematosus
A-Qiong Chen1, A-Xiao Pan1, Juan Liu1
1Department of Rheumatology and Clinical Immunology, Ningbo Medical Center Lihuili Hospital, The Affiliated Li Huili Hospital, Ningbo University, Ningbo, People's Republic of China.
Background:
In this study, we investigated the role of neutrophil-derived exosomal miR-30d-5p in systemic lupus erythematosus (SLE).
Methods:
We extracted exosomes from the neutrophils collected from SLE patients and healthy donors and analyzed the relative level of miR-30d-5p. The exosomes were characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). We mimicked SLE using MRL/lpr mice and treated the mice with exosomes and miR-30d-5p inhibitors. The RNA level of miR-30d-5p in serum of mice was analyzed by qPCR. The images of spleen were captured to evaluate splenomegaly. The serum levels of anti-nuclear antibodies (ANAs), total IgG, total IgM, and anti-dsDNA IgG were measured by ELISA. The kidney injury was analyzed by albumin level, haematoxylin and eosin (HE) staining, active index, and chronic index. The T cell differentiation and B cell activation were detected by flow cytometry. For T follicular helper (TfH) cell analysis, cells were stained with anti-CXCR5 and anti-PD-1 antibodies. Levels of inflammatory cytokines in serum were measured by ELISA.
Results:
The exosomes from SLE patients showed significant higher level of miR-30d-5p. Treatment with neutrophil-exosomes enhanced the degree of splenomegaly in MRL/lpr mice and production of anti-nuclear antibodies (ANAs), total IgG, total IgM, and anti-dsDNA IgG, which was repressed by miR-30d-5p inhibitor. Compared with MRL/lpr mice, mice treated with neutrophil-derive exosomes exhibited a notable increase of proteinuria and infiltration of lymphocytes in kidney, whereas inhibition of miR-30d-5p reduced this elevation. Exosome treatment elevated the number of IL17+ Th17 cells, CXCR5+PD-1+ TfH cells, reduced the portion of Foxp3+ Treg cells, and elevated B cells, and inhibition of miR-30d-5p reversed these effects.
Conclusion:
The neutrophils from SLE exhibited higher level of miR-30d-5p, and inhibition of miR-30d-5p could suppress the T cell and B cell activation, reduce inflammatory cytokine and antibodies production, and alleviate the lupus nephritis during SLE.
Insights
Neutrophil exosomes carry higher levels of miR-30d-5p in systemic lupus erythematosus (SLE). Inhibiting this microRNA can suppress immune cell activation and reduce lupus nephritis severity.
Area of Science:
- Immunology
- Molecular Biology
- Exosome Biology
Background:
- Systemic lupus erythematosus (SLE) is a chronic autoimmune disease.
- Neutrophils play a role in SLE pathogenesis.
- Exosomes are involved in intercellular communication.
Purpose of the Study:
- To investigate the role of neutrophil-derived exosomal miR-30d-5p in SLE.
- To determine if miR-30d-5p in neutrophil exosomes contributes to SLE development.
- To evaluate the therapeutic potential of inhibiting exosomal miR-30d-5p.
Main Methods:
- Exosomes were isolated from neutrophils of SLE patients and healthy donors.
- Exosome characterization using TEM and NTA.
- SLE was modeled in MRL/lpr mice treated with exosomes and miR-30d-5p inhibitors.
- Analysis of immune cell populations, autoantibodies, cytokines, and kidney injury markers.
Main Results:
- Neutrophil exosomes from SLE patients had higher miR-30d-5p levels.
- Exosome treatment exacerbated splenomegaly, autoantibody production, and kidney damage in mice.
- Inhibition of miR-30d-5p reversed these detrimental effects.
- Exosome treatment altered T cell differentiation (increased Th17, TfH; decreased Treg) and B cell activation, which was normalized by miR-30d-5p inhibition.
Conclusions:
- Neutrophil-derived exosomal miR-30d-5p is upregulated in SLE.
- This microRNA promotes immune cell activation and exacerbates lupus nephritis.
- Inhibition of miR-30d-5p shows therapeutic potential for SLE.
