miR-146a Is Differentially Expressed by Myeloid Dendritic Cell Subsets and Desensitizes Cells to TLR2-Dependent Activation

Jurkin, Jennifer; Schichl, Yvonne M.; Koeffel, Rene; Bauer, Thomas; Richter, Susanne; Konradi, Sabine; Geßlbauer, Bernhard; Strobl, Herbert

doi:10.4049/jimmunol.0903021

Cited by 136 publications

(115 citation statements)

References 61 publications

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“…5A), but may also be caused by specific local suppression. For instance, Jurkin et al (18) recently reported that selective overexpression of miR-146a in LCs interfered with TLR2-mediated signaling and caused their nonresponsiveness to PGN. Alternatively, TLR triggering in DCs or skin-resident cells such as keratinocytes, melanocytes, or fibroblasts may have caused the release of suppressive IL-10 to such an extent that it interfered with DC activation.…”

Section: Discussionmentioning

confidence: 99%

Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans

Oosterhoff

Heusinkveld

Lougheed

et al. 2013

The Journal of Immunology

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TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell–mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory capacity. We report that, of six tested TLR-agonists, the TLR2 and -3 agonists peptidoglycan (PGN) and polyribosinic-polyribocytidylic acid (Poly I:C) were uniquely able to enhance the T cell–priming ability of skin-emigrated DCs, which, in the case of PGN, was accompanied by Th1 polarization. The enhanced priming capacity of Poly I:C–stimulated DCs was associated with a strong upregulation of appropriate costimulatory molecules, including CD70, whereas that of PGN-stimulated DCs was associated with the release of a broad array of proinflammatory cytokines. Transcriptional profiling further supported the notion that the PGN- and Poly I:C–induced effects were mediated through binding to TLR2/nucleotide-binding oligomerization domain 2 and TLR3/MDA5, respectively. These data warrant further exploration of PGN and Poly I:C, alone or in combination, as DC-targeted adjuvants for intradermal cancer vaccines.

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Section: Discussionmentioning

confidence: 99%

Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans

Oosterhoff

Heusinkveld

Lougheed

et al. 2013

The Journal of Immunology

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“…miR-146 upregulation has also been confirmed by other independent studies. 55,56 miR-146a induction is controlled by nuclear factor kappaB (NF-kB), which is the most common transcription factor that triggers TLR-induced miRNA transcription. In contrast, miR-155 expression was observed to depend on MyD88-or TRIF-induced JNK activation after TLR stimulation.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

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“…At least in mice deficient in miRNA biogenesis by targeting Dicer (Kuipers et al, 2010b) and Drosha in DC lineages (YZ, unpublished), the pool of LCs was severely diminished. Despite the fact that forced expression of miR-146a does not alter developmental fate, it does reduce TLR2-dependent NFκB signaling (Jurkin et al, 2010). Conversely, knockdown of miR-146a caused an increase in NFκB signaling (Jurkin et al, 2010).…”

Section: Mirnas Affect Differentiation and Funciton Of Other Dcsmentioning

confidence: 96%

“…Despite the fact that forced expression of miR-146a does not alter developmental fate, it does reduce TLR2-dependent NFκB signaling (Jurkin et al, 2010). Conversely, knockdown of miR-146a caused an increase in NFκB signaling (Jurkin et al, 2010). Thus the authors propose that high constitutive miR-146a levels by LCs make them less susceptible to inappropriate activation by commensal bacteria at the body surfaces.…”

Section: Mirnas Affect Differentiation and Funciton Of Other Dcsmentioning

confidence: 97%