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MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression
Ruozhen Hu1, Thomas B Huffaker, Dominique A Kagele
1Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
Abstract:
Th17 cells are central to the pathogenesis of autoimmune disease, and recently specific noncoding microRNAs have been shown to regulate their development. However, it remains unclear whether microRNAs are also involved in modulating Th17 cell effector functions. Consequently, we examined the role of miR-155 in differentiated Th17 cells during their induction of experimental autoimmune encephalomyelitis. Using adoptive transfer experiments, we found that highly purified, myelin oligodendrocyte glycoprotein Ag-specific Th17 cells lacking miR-155 were defective in their capacity to cause experimental autoimmune encephalomyelitis. Gene expression profiling of purified miR-155(-/-)IL-17F(+) Th17 cells identified a subset of effector genes that are dependent on miR-155 for their proper expression through a mechanism involving repression of the transcription factor Ets1. Among the genes reduced in the absence of miR-155 was IL-23R, resulting in miR-155(-/-) Th17 cells being hyporesponsive to IL-23. Taken together, our study demonstrates a critical role for miR-155 in Th17 cells as they unleash autoimmune inflammation and finds that this occurs through a signaling network involving miR-155, Ets1, and the clinically relevant IL-23-IL-23R pathway.
Insights
MicroRNA 155 (miR-155) is crucial for T helper 17 (Th17) cell function in autoimmune diseases. This study reveals miR-155 controls Th17 effector responses by regulating Ets1 and IL-23R, impacting experimental autoimmune encephalomyelitis.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmune Diseases
Background:
- T helper 17 (Th17) cells drive autoimmune pathogenesis.
- MicroRNAs regulate Th17 cell development, but their role in effector functions is unclear.
- miR-155 is a microRNA implicated in immune regulation.
Purpose of the Study:
- To investigate the role of miR-155 in modulating Th17 cell effector functions.
- To determine miR-155's involvement in the induction of experimental autoimmune encephalomyelitis (EAE).
- To elucidate the molecular mechanisms by which miR-155 influences Th17 cell activity.
Main Methods:
- Adoptive transfer of purified Th17 cells lacking miR-155 into recipient mice.
- Induction of experimental autoimmune encephalomyelitis (EAE).
- Gene expression profiling of miR-155 deficient Th17 cells.
- Analysis of the IL-23-IL-23R signaling pathway.
Main Results:
- Th17 cells deficient in miR-155 showed impaired ability to induce EAE.
- miR-155 regulates the expression of effector genes in Th17 cells, including repression of the transcription factor Ets1.
- Absence of miR-155 led to reduced IL-23R expression, causing hyporesponsiveness to IL-23.
Conclusions:
- miR-155 plays a critical role in Th17 cell-mediated autoimmune inflammation.
- The mechanism involves a signaling network including miR-155, Ets1, and the IL-23-IL-23R pathway.
- Targeting miR-155 could be a therapeutic strategy for autoimmune diseases.
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