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Published on: January 7, 2019
miR-146a is differentially expressed by myeloid dendritic cell subsets and desensitizes cells to TLR2-dependent
Jennifer Jurkin1, Yvonne M Schichl, Rene Koeffel
1Center of Physiology, Pathophysiology and Immunology, Institute of Immunology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
Insights
MicroRNA miR-146a, induced by TGF-beta1, is highly expressed in Langerhans cells (LCs) and regulates their immune activation. This finding is crucial for understanding LCs
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Langerhans cells (LCs) and interstitial dendritic cells (intDCs) are related myeloid-derived dendritic cell (DC) subsets with distinct immune functions.
- Understanding the molecular mechanisms of DC subset specification and function is crucial for cell therapy and immunology.
- Current knowledge on the specific molecular regulators of LC and intDC differentiation and function is limited.
Purpose of the Study:
- To investigate the role of microRNA (miRNA) miR-146a in the differentiation and function of human Langerhans cells (LCs) and interstitial dendritic cells (intDCs).
- To identify the regulatory mechanisms controlling miR-146a expression in LCs, particularly in response to microenvironmental signals.
- To determine the functional impact of miR-146a on monocyte and DC activation, focusing on Toll-like receptor (TLR) signaling pathways.
Main Methods:
- Microarray profiling to compare miRNA expression between LCs and intDCs.
- Analysis of miR-146a expression in monocytes and neutrophil granulocytes.
- Investigating the role of transcription factor PU.1 and TGF-beta1 in inducing miR-146a expression in LCs.
- Functional studies involving ectopic expression or silencing of miR-146a in monocytes and DCs to assess its impact on TLR2 signaling and cytokine production.
Main Results:
- miR-146a is constitutively expressed at higher levels in human LCs compared to intDCs, monocytes, and neutrophil granulocytes.
- Epidermal microenvironmental signals, specifically TGF-beta1, induce high miR-146a expression in LCs via the transcription factor PU.1.
- Ectopic miR-146a in monocytes and intDCs inhibits TLR2-mediated downstream signaling and cytokine production without affecting DC maturation.
- Silencing miR-146a in LCs enhances TLR2-dependent NF-kappaB signaling, indicating miR-146a's inhibitory role.
Conclusions:
- High constitutive miR-146a levels in LCs are induced by epidermal microenvironmental signals.
- miR-146a acts as a regulator of monocyte and DC activation, specifically modulating TLR2 signaling.
- The elevated miR-146a in LCs may protect them from inappropriate activation by commensal bacterial TLR2 triggers at body surfaces.
Abstract:
Langerhans cells (LCs) in epithelia and interstitial dendritic cells (intDCs) in adjacent connective tissues represent two closely related myeloid-derived DC subsets that exert specialized functions in the immune system and are of clinical relevance for cell therapy. Both subsets arise from monocyte-committed intermediates in response to tissue-associated microenvironmental signals; however, molecular mechanisms underlying myeloid DC subset specification and function remain poorly defined. Using microarray profiling, we identified microRNA (miRNA) miR-146a to be constitutively expressed at higher levels in human LCs compared with intDCs. Moreover, miR-146a levels were low in monocytes and nondetectable in neutrophil granulocytes. Interestingly, constitutive high miR-146a expression in LCs is induced by the transcription factor PU.1 in response to TGF-beta1, a key microenvironmental signal for epidermal LC differentiation. We identified miR-146a as a regulator of monocyte and DC activation but not myeloid/DC subset differentiation. Ectopic miR-146a in monocytes and intDCs interfered with TLR2 downstream signaling and cytokine production, without affecting phenotypic DC maturation. Inversely, silencing of miR-146a in LCs enhanced TLR2-dependent NF-kappaB signaling. We therefore conclude that high constitutive miR-146a levels are induced by microenvironmental signals in the epidermis and might render LCs less susceptible to inappropriate activation by commensal bacterial TLR2 triggers at body surfaces.
