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Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential.

DelaRosa O, Lombardo E - Mediators Inflamm. (2010)

Bottom Line: Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities.Notably, activation by TLR ligands has not been reported to modulate the "immunoprivileged" phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies.In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling.

View Article: PubMed Central - PubMed

Affiliation: Cellerix S.A, Parque Tecnológico de Madrid, Calle Marconi 1, Tres Cantos, Madrid, Spain.

ABSTRACT
Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the "immunoprivileged" phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling.

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TLR signalling. Ligand recognition results in the recruitment of intracellular TIR-domain-containing adaptors proteins, including myeloid-differentiation primary-response protein 88 (MyD88, shared by all TLRs, except TLR3), and Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF, employed by TLR3 and TLR4). Engagement of MyD88 activates a signaling cascade including IL-1R-associated kinases (IRAKs,), (TNF)-receptor-associated factor 6 (TRAF6) and transforming growth factor-β (TGF-β)-activated kinase (TAK1), leading to the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38, and nuclear translocation of the transcription factor nuclear factor-κB (NF-κB) (MyD88-dependent pathway). There is a  second, alternative pathway triggered by TRIF (MyD88-independent pathway) that culminates in the activation of NF-κB, MAPKs, and the transcription factors interferon-responsive factors (IRFs), whose are responsible for induction of type I IFNs, in particular IFNβ. Besides MyD88 and TRIF, two other adaptor proteins have been described: TIR-domain-containing adaptor protein (TIRAP, also called MAL), and TRIF-related adaptor molecule (TRAM, required for TRIF-dependent signaling through TLR4, but not TLR3).
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fig1: TLR signalling. Ligand recognition results in the recruitment of intracellular TIR-domain-containing adaptors proteins, including myeloid-differentiation primary-response protein 88 (MyD88, shared by all TLRs, except TLR3), and Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF, employed by TLR3 and TLR4). Engagement of MyD88 activates a signaling cascade including IL-1R-associated kinases (IRAKs,), (TNF)-receptor-associated factor 6 (TRAF6) and transforming growth factor-β (TGF-β)-activated kinase (TAK1), leading to the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38, and nuclear translocation of the transcription factor nuclear factor-κB (NF-κB) (MyD88-dependent pathway). There is a second, alternative pathway triggered by TRIF (MyD88-independent pathway) that culminates in the activation of NF-κB, MAPKs, and the transcription factors interferon-responsive factors (IRFs), whose are responsible for induction of type I IFNs, in particular IFNβ. Besides MyD88 and TRIF, two other adaptor proteins have been described: TIR-domain-containing adaptor protein (TIRAP, also called MAL), and TRIF-related adaptor molecule (TRAM, required for TRIF-dependent signaling through TLR4, but not TLR3).

Mentions: As reviewed extensively somewhere else in this issue, TLR activation trigger MyD88 dependent and independent downstream signalling cascades leading to the nuclear translocation of NF-κB and other transcription factors and the activation of a number of genes (see Figure 1) [47–52]. It has been demonstrated that when AD-MSCs or BM-MSCs were stimulated with ligands specific for different TLRs the nuclear factor-kappa B (NF-κB), mitogen-activated protein (MAP) kinases (MAPKs), PI3K signalling pathways were activated with a subsequent induction of several genes and cytokines, mainly CXCL-10, IL-6 and IL-8. These results clearly demonstrate that MSC express active and functional TLRs. However, differences in the induction of genes in response to TLR activation have been reported. For instance, in contrast to our observations in AD-MSC, Hwa Cho et al., and Tomchuck et al. have reported the induction of tumor necrosis factor (TNF)-α and IL-1β by LPS and polyinosinic:polycytidylic acid (Poly IC) in BM-MSC and AD-MSC, respectively [44, 53].


Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential.

DelaRosa O, Lombardo E - Mediators Inflamm. (2010)

TLR signalling. Ligand recognition results in the recruitment of intracellular TIR-domain-containing adaptors proteins, including myeloid-differentiation primary-response protein 88 (MyD88, shared by all TLRs, except TLR3), and Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF, employed by TLR3 and TLR4). Engagement of MyD88 activates a signaling cascade including IL-1R-associated kinases (IRAKs,), (TNF)-receptor-associated factor 6 (TRAF6) and transforming growth factor-β (TGF-β)-activated kinase (TAK1), leading to the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38, and nuclear translocation of the transcription factor nuclear factor-κB (NF-κB) (MyD88-dependent pathway). There is a  second, alternative pathway triggered by TRIF (MyD88-independent pathway) that culminates in the activation of NF-κB, MAPKs, and the transcription factors interferon-responsive factors (IRFs), whose are responsible for induction of type I IFNs, in particular IFNβ. Besides MyD88 and TRIF, two other adaptor proteins have been described: TIR-domain-containing adaptor protein (TIRAP, also called MAL), and TRIF-related adaptor molecule (TRAM, required for TRIF-dependent signaling through TLR4, but not TLR3).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2902124&req=5

fig1: TLR signalling. Ligand recognition results in the recruitment of intracellular TIR-domain-containing adaptors proteins, including myeloid-differentiation primary-response protein 88 (MyD88, shared by all TLRs, except TLR3), and Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF, employed by TLR3 and TLR4). Engagement of MyD88 activates a signaling cascade including IL-1R-associated kinases (IRAKs,), (TNF)-receptor-associated factor 6 (TRAF6) and transforming growth factor-β (TGF-β)-activated kinase (TAK1), leading to the activation of the mitogen-activated protein (MAP) kinases ERK, JNK, and p38, and nuclear translocation of the transcription factor nuclear factor-κB (NF-κB) (MyD88-dependent pathway). There is a second, alternative pathway triggered by TRIF (MyD88-independent pathway) that culminates in the activation of NF-κB, MAPKs, and the transcription factors interferon-responsive factors (IRFs), whose are responsible for induction of type I IFNs, in particular IFNβ. Besides MyD88 and TRIF, two other adaptor proteins have been described: TIR-domain-containing adaptor protein (TIRAP, also called MAL), and TRIF-related adaptor molecule (TRAM, required for TRIF-dependent signaling through TLR4, but not TLR3).
Mentions: As reviewed extensively somewhere else in this issue, TLR activation trigger MyD88 dependent and independent downstream signalling cascades leading to the nuclear translocation of NF-κB and other transcription factors and the activation of a number of genes (see Figure 1) [47–52]. It has been demonstrated that when AD-MSCs or BM-MSCs were stimulated with ligands specific for different TLRs the nuclear factor-kappa B (NF-κB), mitogen-activated protein (MAP) kinases (MAPKs), PI3K signalling pathways were activated with a subsequent induction of several genes and cytokines, mainly CXCL-10, IL-6 and IL-8. These results clearly demonstrate that MSC express active and functional TLRs. However, differences in the induction of genes in response to TLR activation have been reported. For instance, in contrast to our observations in AD-MSC, Hwa Cho et al., and Tomchuck et al. have reported the induction of tumor necrosis factor (TNF)-α and IL-1β by LPS and polyinosinic:polycytidylic acid (Poly IC) in BM-MSC and AD-MSC, respectively [44, 53].

Bottom Line: Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities.Notably, activation by TLR ligands has not been reported to modulate the "immunoprivileged" phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies.In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling.

View Article: PubMed Central - PubMed

Affiliation: Cellerix S.A, Parque Tecnológico de Madrid, Calle Marconi 1, Tres Cantos, Madrid, Spain.

ABSTRACT
Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the "immunoprivileged" phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling.

Show MeSH
Related in: MedlinePlus