Modulation of Adult Mesenchymal Stem Cells Activity by Toll-Like Receptors: Implications on Therapeutic Potential

Figure 1

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-$\beta$ (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-$\beta$ (TGF-$\beta$)-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-$\kappa$B (NF-$\kappa$B) (MyD88-dependent pathway). There is a second, alternative pathway triggered by TRIF (MyD88-independent pathway) that culminates in the activation of NF-$\kappa$B, MAPKs, and the transcription factors interferon-responsive factors (IRFs), whose are responsible for induction of type I IFNs, in particular IFN$\beta$. 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).