The Role of Toll-Like Receptors in Autoimmune Diseases through Failure of the Self-Recognition Mechanism

Abstract

Toll-like receptors (TLRs), part of the innate immune system that recognises molecular signatures, are important in the recognition of pathogenic components. However, when specific cellular contexts develop in which TLRs are inappropriately activated by self-components, this may lead to sterile inflammation and result in the occurrence of autoimmunity. This review analyses the available data regarding TLR biochemistry, the specific mechanisms which are brought about by TLR activation, and the importance of these mechanisms in the light of any existing and potential therapies in the field of autoimmunity.

Figure 1

TLR signalling pathways. The two main pathways by which TLR signalling occurs upon stimulation by their ligands. These pathways are characterised depending on which of the adaptor molecules MyD88 or TRIF are involved. These signalling cascades result in the activation of NF-kB, IRFs, and MAP kinases, which promote the transcription of various immune response genes, including inflammatory cytokines and IFNγ-related genes. (AP-1, activator protein 1; ERK, extracellular signal-regulated kinase; IKK, inhibitor of kappa light polypeptide gene enhancer in B-cell kinase; IRAK, IL-1 receptor-associated kinase; JNK, c-Jun N-terminal kinase; MKK, MAPK kinase; RIP1, receptor interacting protein 1; TAK, transforming growth factor-activated kinase; TBK1, TANK-binding kinase 1; TRAF, tumour necrosis factor receptor-associated factor.)

Figure 2

TLR signalling inhibitors. The regulation of TLR signalling has been achieved through the application of both natural and synthetic inhibitory molecules, which target each of the key molecules in the TLR signalling pathways, acting through a wide range of mechanisms. (AP-1, activator protein 1; ATF, activating transcription factor; ERK, extracellular signal-regulated kinase; IKK, inhibitor of kappa light polypeptide gene enhancer in B-cell kinase; IRAK, IL-1 receptor-associated kinase; JNK, c-Jun N-terminal kinase; MKK, MAPK kinase; RIP1, receptor interacting protein 1; TAB, transforming growth factor-b-activated kinase 1/MAP3K7-binding protein; TAK, transforming growth factor-activated kinase; TRAF, tumour necrosis factor receptor-associated factor); A20, Tumour Necrosis Factor Inducible Protein A20; ATF3, Activating Transcription Factor 3; Bcl-3, B-Cell Lymphoma 3-Encoded Protein; Cbl-b, E3 Ubiquitin Protein Ligase Cbl-b; CYLD, Ubiquitin-Specific-Processing Protease CYLD; DUBA, Deubiquitinating Enzyme A; HA900, high molecular weight hyaluronan; IkBNS, NF-κB Inhibitor Delta; Nurr1, Nuclear Receptor Related 1; PDLIM2, PDZ and LIM Domain Protein 2; PIN1, Peptidylprolyl Cis/Trans Isomerase, NIMA-Interacting 1; SARM, Sterile Alpha and TIR Motif Containing 1; SHP, Small Heterodimer Partner; SOCS1, Suppressor of Cytokine Signalling 1; SOCS3, Suppressor of Cytokine Signalling 3; TAG, splice variant of the adaptor TRAM; TANK, TRAF Family Member Associated NF-κB Activator; TRIM5, Tripartite Motif Containing 5; TRIM38, Tripartite Motif Containing Protein 38; UBE3C, Ubiquitin Protein Ligase E3C; USP4, Ubiquitin Specific Peptidase 4.