Abstract
Toll-like receptors (TLRs) recognize molecules specific to pathogens and endogenous danger signals. Binding of agonists to the ectodomain of the receptor initiates TLR activation and is followed by the association of receptor cytosolic Toll/Interleukin-1 receptor (TIR) domains with TIR domains of adapter proteins leading to the assembly of signaling cascade of protein kinases that ultimately trigger the activation of transcription factors and expression of genes involved in the immune response. Excessive activation of TIR-domain mediated signaling has been implicated in inflammatory diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, colitis) as well as in the development of cancer. Targeting receptor-adapter interactions represents a potential strategy for the therapeutic TLR/IL-1R-specific inhibition due to the unique interacting domains involved. Peptide and protein-domain binding TLR inhibitors originating from the interacting surfaces of TIR-domain containing proteins can bind to the site on their target interacting protein thereby preventing the assembly of the functional signaling complex. Here we review protein-domain, peptide and peptidomimetic inhibitors targeting TIR-domain mediated interactions and their application demonstrated on in vitro and in vivo models. Recent structural data and elucidation of the molecular mechanisms of TIR-domain mediated signaling enabled the development of peptide inhibitors from TIR domains of TLRs and adapters, MyD88 intermediary domain as well as improved protein inhibitors based on TIR domain dimerization, mimicking bacterial TIR-domain containing immunosuppressors (TCPs) which we discuss with challenges concerning the delivery and specificity of inhibitors targeting TLR adapters.
Highlights
Innate immunity represents the first defense line of the host against pathogenic microbes providing the immediate immune response [1, 2]
Innate immune response is mediated by phagocytes such as macrophages and dendritic cells which discriminate between the self molecules and pathogens using pathogen recognition receptors (PRRs) which are able to detect the unique and conserved components of pathogens known as pathogen associated molecular patterns (PAMPs)
Downstream Toll-like receptors (TLRs) signaling is mediated by the conserved cytosolic Toll/IL-1 receptor domain (TIR) domain [13,14,15] present in TLR/IL-1R and in TLR adapter proteins which bridge the TLRs to the proteins of the subsequent signaling cascade leading to expression of genes involved in innate immune response
Summary
Innate immunity represents the first defense line of the host against pathogenic microbes providing the immediate immune response [1, 2]. Activation of TLR signaling pathways induces activation of the innate immune response by expression of defense molecules and primes the development of adaptive response [5, 6]. The engagement of TLR7 and TLR9 MyD88 dependent pathways induces the secretion of inflammatory cytokines due to the activation of NF-kB and the expression of type I IFNs through the activation of IRF7 [26]. MyD88-independent pathway on the other hand engages adapter TRIF that activates NF-kB through the C-terminal part of TRIF interacting with RIP or through its N-terminal part through TRAF6 culminating in inflammatory cytokine production [27]. The activation of TRIF dependent pathway results in the production of type I IFNs triggered by the activation of IRF3 induced by TBK1 kinase through the N-terminal part of TRIF [28, 29]
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