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MicroRNA-146a controls Th1-cell differentiation of human CD4+ T lymphocytes by targeting PRKCε
Patrick Möhnle1, Stefanie V Schütz, Verena van der Heide
1Research Group Molecular Medicine, Department of Anesthesiology, University of Munich (LMU), Munich, Germany.
Abstract:
T-cell functions must be tightly controlled to keep the balance between vital proinflammatory activity and detrimental overactivation. MicroRNA-146a (miR-146a) has been identified as a key negative regulator of T-cell responses in mice. Its role in human T cells and its relevance to human inflammatory disease, however, remains poorly defined. In this study, we have characterized miR-146a-driven pathways in primary human T cells. Our results identify miR-146a as a critical gatekeeper of Th1-cell differentiation processes acting via molecular mechanisms not uncovered so far. MiR-146a targets protein kinase C epsilon (PRKCε), which is part of a functional complex consisting of PRKCε and signal transducer and activator of transcription 4 (STAT4). Within this complex, PRKCε phosphorylates STAT4, which in turn is capable of promoting Th1-cell differentiation processes in human CD4(+) T lymphocytes. In addition, we observed that T cells of sepsis patients had reduced levels of miR-146a and an increased PRKCε expression in the initial hyperinflammatory phase of the disease. Collectively, our results identify miR-146a as a potent inhibitor of Th1-cell differentiation in human T cells and suggest that dysregulation of miR-146a contributes to the pathogenesis of sepsis.
Insights
MicroRNA-146a (miR-146a) inhibits Th1-cell differentiation in human T cells by targeting protein kinase C epsilon (PRKCε). Reduced miR-146a and increased PRKCε are observed in sepsis patients.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- T-cell function requires strict regulation to balance inflammation and prevent overactivation.
- MicroRNA-146a (miR-146a) is a known regulator of T-cell responses in mice.
- The role of miR-146a in human T cells and inflammatory diseases is not well understood.
Purpose of the Study:
- To investigate the function and molecular mechanisms of miR-146a in primary human T cells.
- To determine the relevance of miR-146a dysregulation in human inflammatory conditions like sepsis.
Main Methods:
- Characterization of miR-146a-driven pathways in human CD4(+) T cells.
- Identification of miR-146a targets and their interacting partners.
- Analysis of miR-146a and PRKCε levels in T cells from sepsis patients.
Main Results:
- MiR-146a acts as a critical regulator of Th1-cell differentiation in human T cells.
- MiR-146a directly targets protein kinase C epsilon (PRKCε).
- PRKCε, in complex with STAT4, promotes Th1-cell differentiation.
- Sepsis patients exhibit decreased miR-146a and increased PRKCε during the hyperinflammatory phase.
Conclusions:
- MiR-146a is a potent inhibitor of Th1-cell differentiation in humans.
- Dysregulation of miR-146a is implicated in the pathogenesis of sepsis.
- The miR-146a/PRKCε/STAT4 pathway is a novel mechanism controlling human T-cell responses.
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