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MicroRNA-448 promotes multiple sclerosis development through induction of Th17 response through targeting protein
Rihan Wu1, Qinyu He2, Haitao Chen1
1Department of Gerontology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
Abstract:
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system, and its pathogenesis remains largely unclear. Much attention has been paid to the role of microRNAs (miRs) in regulation of autoimmune disease. Here, we found, for the first time, that miR-448 expression was significantly increased in periphery blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) of patients with MS, and its expression positively correlated with the disease severity. We further demonstrated that CD4+ T cells, especially the Th17 lineage, were the major source of miR-448 expression. Using gain- and loss-of-function approaches, we further verified that miR-448 could enhance Th17 differentiation, characterized by up-regulated expression levels of IL-17A and RORγt. Interleukin (IL)-1β as a potent driver of pathogenic Th17 cells was able to strongly induce miR-448 expression in CD4+ T cells through activating NF-κB pathway. Additionally, we identified that miR-448 directly targeted protein tyrosine phosphatase non-receptor type 2 (PTPN2), which has been known as an anti-inflammatory player with capacity to suppress Th17 differentiation. We also observed markedly decreased expression of PTPN2 in PBMC and CSF of MS patients. Our results suggest that miR-448 might promote Th17 differentiation in MS and thus aggravate the disease through inhibiting PTPN2.
Insights
MicroRNA-448 is elevated in multiple sclerosis (MS) patients, promoting harmful Th17 cell differentiation and potentially worsening the disease by inhibiting PTPN2. This finding offers new insights into MS pathogenesis.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Multiple sclerosis (MS) is a central nervous system autoimmune disease with unclear pathogenesis.
- MicroRNAs (miRs) are increasingly recognized for their role in regulating autoimmune diseases.
Purpose of the Study:
- To investigate the role of miR-448 in the pathogenesis of multiple sclerosis.
- To explore the regulatory mechanisms of miR-448 in CD4+ T cell differentiation.
Main Methods:
- Quantification of miR-448 expression in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) from MS patients.
- Analysis of miR-448 expression in CD4+ T cells, particularly Th17 cells.
- Gain- and loss-of-function experiments to assess miR-448's impact on Th17 differentiation.
- Investigation of the regulatory pathway involving Interleukin-1β (IL-1β) and NF-κB.
- Identification of PTPN2 as a direct target of miR-448.
Main Results:
- miR-448 expression was significantly increased in MS patients' PBMC and CSF, correlating with disease severity.
- CD4+ T cells, especially Th17 cells, were identified as the primary source of miR-448.
- miR-448 enhanced Th17 differentiation, increasing IL-17A and RORγt levels.
- IL-1β induced miR-448 expression in CD4+ T cells via the NF-κB pathway.
- miR-448 directly targeted and inhibited PTPN2, an anti-inflammatory molecule.
- PTPN2 expression was decreased in MS patients' PBMC and CSF.
Conclusions:
- miR-448 promotes Th17 cell differentiation in multiple sclerosis.
- The miR-448/PTPN2 axis may contribute to MS pathogenesis by exacerbating inflammation.
- Targeting miR-448 could be a potential therapeutic strategy for MS.
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