Cutting Edge: MicroRNA-223 Regulates Myeloid Dendritic Cell-Driven Th17 Responses in Experimental Autoimmune
Igal Ifergan1,2, Siqi Chen1,3, Bin Zhang1,3
1Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Abstract:
Myeloid cells play a crucial role in the induction and sustained inflammation in neuroinflammatory disorders, such as multiple sclerosis. miR-223, a myeloid cell-specific microRNA, is one of the most upregulated microRNAs in multiple sclerosis patients. We demonstrate that miR-223-knockout mice display significantly reduced active and adoptive-transfer experimental autoimmune encephalomyelitis that is characterized by reduced numbers of myeloid dendritic cells (mDCs) and Th17 cells in the CNS. Knockout mDCs have increased PD-L1 and decreased IL-1β, IL-6, and IL-23 expression, as well as a reduced capacity to drive Th17, but not Th1, cell differentiation. Thus, miR-223 controls mDC-induced activation of pathologic Th17 responses during autoimmune inflammation.
Insights
MicroRNA-223 (miR-223) drives neuroinflammation in multiple sclerosis by promoting myeloid dendritic cell activation. Removing miR-223 reduces disease severity and pathogenic Th17 cell responses in the central nervous system.
Area of Science:
- Neuroimmunology
- Molecular biology
- MicroRNA research
Background:
- Myeloid cells are key drivers of neuroinflammation in disorders like multiple sclerosis.
- MicroRNA-223 (miR-223) is significantly upregulated in multiple sclerosis patients and is specific to myeloid cells.
Purpose of the Study:
- To investigate the role of miR-223 in myeloid cell-driven neuroinflammation and experimental autoimmune encephalomyelitis (EAE).
- To determine how miR-223 influences myeloid dendritic cell (mDC) function and subsequent T cell differentiation.
Main Methods:
- Utilized miR-223-knockout mice to model experimental autoimmune encephalomyelitis (EAE).
- Analyzed immune cell populations, including myeloid dendritic cells (mDCs) and T helper 17 (Th17) cells, in the central nervous system (CNS).
- Assessed mDC phenotype, cytokine expression (IL-1β, IL-6, IL-23), PD-L1 levels, and their capacity to induce Th17 and Th1 cell differentiation.
Main Results:
- miR-223-knockout mice exhibited significantly reduced active and adoptive-transfer EAE.
- CNS analysis revealed decreased numbers of mDCs and Th17 cells in knockout mice.
- Knockout mDCs showed increased PD-L1 expression and reduced IL-1β, IL-6, and IL-23 production.
- mDCs from knockout mice had a diminished capacity to drive Th17 cell differentiation, while Th1 cell differentiation remained unaffected.
Conclusions:
- miR-223 is a critical regulator of pathogenic Th17 responses in autoimmune neuroinflammation.
- Targeting miR-223 in myeloid cells may offer a therapeutic strategy for multiple sclerosis and related disorders.
