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MicroRNA-155 Plays Selective Cell-Intrinsic Roles in Brain-Infiltrating Immune Cell Populations during
Jacob W Thompson1, Ruozhen Hu1, Thomas B Huffaker1
1Department of Pathology, Division of Microbiology and Immunology, University of Utah, Salt Lake City, UT.
Abstract:
The proinflammatory microRNA-155 (miR-155) is highly expressed in the serum and CNS lesions of patients with multiple sclerosis (MS). Global knockout (KO) of miR-155 in mice confers resistance to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), by reducing the encephalogenic potential of CNS-infiltrating Th17 T cells. However, cell-intrinsic roles for miR-155 during EAE have not been formally determined. In this study, we use single-cell RNA sequencing and cell-specific conditional miR-155 KOs to determine the importance of miR-155 expression in distinct immune cell populations. Time-course single-cell sequencing revealed reductions in T cells, macrophages, and dendritic cells (DCs) in global miR-155 KO mice compared with wild-type controls at day 21 after EAE induction. Deletion of miR-155 in T cells, driven by CD4 Cre, significantly reduced disease severity similar to global miR-155 KOs. CD11c Cre-mediated deletion of miR-155 in DCs also resulted in a modest yet significant reduction in the development of EAE, with both T cell- and DC-specific KOs showing a reduction in Th17 T cell infiltration into the CNS. Although miR-155 is highly expressed in infiltrating macrophages during EAE, deletion of miR-155 using LysM Cre did not impact disease severity. Taken together, these data show that although miR-155 is highly expressed in most infiltrating immune cells, miR-155 has distinct roles and requirements depending on the cell type, and we have demonstrated this using the gold standard conditional KO approach. This provides insights into which functionally relevant cell types should be targeted by the next generation of miRNA therapeutics.
Insights
MicroRNA-155 (miR-155) drives multiple sclerosis (MS) severity. Conditional knockout in T cells and dendritic cells reduced experimental autoimmune encephalomyelitis (EAE) in mice, highlighting cell-specific therapeutic targets.
Area of Science:
- Immunology
- Neuroscience
- Genetics
Background:
- MicroRNA-155 (miR-155) is a proinflammatory microRNA implicated in multiple sclerosis (MS).
- Global knockout of miR-155 in mice confers resistance to experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.
- The cell-intrinsic roles of miR-155 in distinct immune cell populations during EAE remain undetermined.
Purpose of the Study:
- To investigate the cell-specific roles of miR-155 in immune cells during the development of EAE.
- To determine the impact of miR-155 deletion in T cells, macrophages, and dendritic cells (DCs) on EAE pathogenesis.
- To identify specific immune cell types where miR-155 plays a critical role in MS.
Main Methods:
- Utilized single-cell RNA sequencing to analyze immune cell populations in global miR-155 knockout (KO) mice.
- Employed cell-specific conditional miR-155 KO mouse models (CD4 Cre for T cells, CD11c Cre for DCs, LysM Cre for macrophages).
- Assessed disease severity and CNS-infiltrating Th17 T cell levels in various conditional KO models during EAE induction.
Main Results:
- Global miR-155 KO mice showed reduced T cells, macrophages, and DCs at day 21 post-EAE induction.
- Conditional deletion of miR-155 in T cells significantly reduced EAE severity, mirroring global KO effects.
- Deletion of miR-155 in DCs also led to a significant reduction in EAE, with decreased Th17 T cell infiltration.
- miR-155 deletion in macrophages did not affect EAE severity, despite its high expression in these cells during EAE.
Conclusions:
- miR-155 plays distinct, cell-type-dependent roles in the pathogenesis of EAE.
- T cells and dendritic cells are key immune cell types where miR-155 contributes to MS pathogenesis.
- Targeting miR-155 in specific immune cells, particularly T cells and DCs, represents a promising therapeutic strategy for MS.
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