Expression of toll‐like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL‐8 release, and up‐regulation of NKG2D‐ligands

Schreiner, Bettina; Voss, Joachim; Wischhusen, Jörg; Dombrowski, Yvonne; Steinle, Alexander; Lochmüller, Hanns; Dalakas, Marinos C.; Melms, Arthur; Wiendl, Heinz

doi:10.1096/fj.05-4342fje

Cited by 83 publications

(73 citation statements)

References 63 publications

(82 reference statements)

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“…Recent publications have shown that cell expression of NKG2D ligands was induced by signaling through TLRs (51,52). There is accumulated evidence that human placenta expresses TLR-2, TLR-3, and TLR-4 (53).…”

Section: Discussionmentioning

confidence: 99%

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function

Hedlund¹,

Stenqvist²,

Nagaeva³

et al. 2009

The Journal of Immunology

284

266

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During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1–5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1–5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8+, and γδ T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ.

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Section: Discussionmentioning

confidence: 99%

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function

Hedlund¹,

Stenqvist²,

Nagaeva³

et al. 2009

The Journal of Immunology

284

266

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“…20 Interleukin-6 (IL-6) production in response to lipopolysaccharide by human 21 and murine 22 myoblasts suggested that skeletal muscle cells express specific TLRs. 23,24 As a matter of fact, the expression of TLR2, involved in the response to peptidoglycan and lipoproteins/lipopeptides, 25 TLR4, which recognizes LPS from Gram-negative bacteria, 24 TLR5, which recognizes flagellin from Gram-negative outer membrane, 26 TLR3, which recognizes double-stranded (ds) RNA, suggesting a role in viral recognition, 27 and TLR9, which recognizes unmethylated CpG oligodeoxynucleotides, DNA motifs that are found more commonly in bacterial and viral genomes has been demonstrated ( Figure 1a). 25 TLR2, TLR4, TLR5 and TLR9 mRNA expression has been found in murine differentiated myotubes as well as in muscles; interestingly, TLR2 and TLR5 were expressed only in murine differentiated myotubes, but not in myoblasts, indicating that the expression of these TLRs is regulated by skeletal muscle cell differentiation.…”

Section: Toll-like Receptor Function In Muscle Cellsmentioning

confidence: 99%

“…29 The stimulation with Poli(I:C) (an analogue of dsRNA) and interferon-g (IFN-g) upregulates the expression of TLR-3 mRNA in cultured human myoblasts, inducing nuclear factor-kB activation and IL-8 secretion; TLR3 was also detected in biopsies from inflamed and non-inflamed human muscles. 23 TLRs may therefore represent the immune trigger following DNA injection in muscles: vector CpG motifs can act as adjuvants similarly to bacterial CpG, inducing activation of professional APCs, while directly stimulating muscle cell-mediated immune response. 30 Mammalian, bacterial, plasmid and synthetic DNA containing unmethylated CpG dinucleotides in specific sequence contexts are recognized by TLR9 on B cells and on plasmacytoid DCs, triggering IL-12, tumour necrosis factor (TNF)a and IFNa secretion, a critical step in cellular immune response.…”

Section: Toll-like Receptor Function In Muscle Cellsmentioning

confidence: 99%

Skeletal muscle cells: from local inflammatory response to active immunity

et al. 2010

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The skeletal muscles are the major living component of the human body. They are constituted by stable cells, the myofibres, and by adult multipotent stem cells, the satellite cells, which can multiply to regenerate and repair the damaged tissues. Injections of DNA in muscle cells have been used to produce recombinant proteins with opposite goals: somatic reparation of genetic defects, which needs to elicit no inflammatory or immune response, and DNA vaccination, which needs a robust immune response. Because of possible therapeutical interventions, a growing body of information is being produced dealing with every aspect of the myofibres during inflammatory and autoimmune responses: skeletal muscle-antigen presenting cell (APC) interaction and intrinsic APC capabilities of myoblasts and myocytes, the response to released cytokines and their endogenous production, the regulation of Toll-like receptors and major histocompatibility complex expression. According to these data, the muscle tissue is now emerging no longer as a passive bystander, but more as an active player that, when correctly manipulated, can drive tolerance or immunization to these de novo produced proteins. In the present review, we summarize the recent developments on the control of muscle immune function.

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“…In human skeletal muscle cell lines such as myoblasts and human rhabdomyosarcoma cells (TE671), there are low mRNA expression of TLR1-7 and TLR9 but constitutively expression of TLR3 which can be up-regulated by poly(I : C) [90]. Moreover, TLR3 engagement with poly(I : C) or other dsRNA is capable of initiating the increase of NKG2D on NK cells, and also the up-regulation of respective ligands such as MICA, MICB, ULBP-2 and ULBP-3 in human muscle cells [91].…”

Section: The Crosstalk Between Tlr and Nk Cell Receptorsmentioning

confidence: 99%

“…Moreover, TLR3 engagement with poly(I : C) or other dsRNA is capable of initiating the increase of NKG2D on NK cells, and also the up-regulation of respective ligands such as MICA, MICB, ULBP-2 and ULBP-3 in human muscle cells [91]. The interaction between NKG2D and ligands results in autologous cytotoxicity and the secretion of IL-8 and tissue inhibitor of metalloproteinase-2 (TIMP-2), which can aggravate the development of sarcolysis [90]. The activation of TLR signaling also breaks down epithelial homeostasis of small intestine in mice.…”

Section: The Crosstalk Between Tlr and Nk Cell Receptorsmentioning

confidence: 99%

Critical role of Toll-like receptor signaling in NK cell activation

Guo

Zhang

2012

Chin. Sci. Bull.

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Toll-like receptors (TLRs) and NK cell receptors are the most important receptor superfamilies in innate immunity. TLRs act as the sensor of external pathogens, while NK cells detect alterations in endogenous protein expression on target cells through activating and inhibitory receptors. Accumulating data has demonstrated that TLRs and NK cell receptors can coordinate and regulate each other during immune responses, which contributes to the initiation of innate response and the priming of adaptive responses. TLRs can activate NK cell function directly or with the help of accessory cells in a cytokine or cell-to-cell contact dependent manner. More understanding of the recognition of innate receptors and interactions between them may provide important insights into the design of effective strategies to combat tumor and microbial infections. In this review, we summarize how TLRs and NK cells discriminate the self or non-self components respectively. And importantly, we pay more attention to the role of TLR signaling in induction of NK cell activation, responses and the crosstalk between them. Toll-like receptor, natural killer (NK) cells, NK cell receptor, dendritic cells, crosstalk Citation:Guo Q, Zhang C. Critical role of Toll-like receptor signaling in NK cell activation.

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Expression of toll‐like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL‐8 release, and up‐regulation of NKG2D‐ligands

Cited by 83 publications

References 63 publications

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function

Skeletal muscle cells: from local inflammatory response to active immunity

Critical role of Toll-like receptor signaling in NK cell activation

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