The critical role of toll-like receptors--From microbial recognition to autoimmunity: A comprehensive review

Abstract

Toll-like receptors (TLRs) constitute an important mechanism in the activation of innate immune cells including monocytes, macrophages and dendritic cells. Macrophage activation by TLRs is pivotal in the initiation of the rapid expression of pro-inflammatory cytokines TNF, IL-1β and IL-6 while promoting Th17 responses, all of which play critical roles in autoimmunity. Surprisingly, in inflammatory arthritis, activation of specific TLRs can not only induce but also inhibit cellular processes associated with bone destruction. The intercellular and intracellular orchestration of signals from different TLRs, their endogenous or microbial ligands and accessory molecules determine the activating or inhibitory responses. Herein, we review the TLR-mediated activation of innate immune cells in their activation and differentiation to osteoclasts and the capacity of these signals to contribute to bone destruction in arthritis. Detailed understanding of the opposing mechanisms of TLRs in the induction and suppression of cellular processes in arthritis may pave the way to develop novel therapies to treat autoimmunity.

Keywords: Innate immunity; Osteoclasts; Rheumatoid arthritis; Toll-like receptors.

Figure 1. Crystal structure of TLR receptors

A) Crystal structure of hTLR2ED/hTLR1ED (human TLR2 ectodomain/ human TLR1 ectodomain) in complex with Pam3CSK4. hTLR2ED is shown in blue, hTLR1ED in green. Pam3CSK4 is in red. This figure was generated from PDB code 2Z7X [16]. B) Crystal structure of hTLR4ED/hMD-2 in complex with LPS. hTLR4ED is shown in green hMD-2 in blue, LPS is in red. This figure was generated from PDB code 3FXI [23] C) Crystal structure of zebrafish TLR5ED (zTLR5ED) in complex with flagellin. zTLR5ED is depicted in green and flagellin in red. This figure was generated from PDB code 3v47 [27]. D) Crystal structure of mouse TLR3ED (mTLR3ED) in complex with dsRNA. mTLR3ED is depicted in green while dsRNA is in red. This figure was generated from PDB code 3CIY [23]. E) Crystal structure of hTLR8ED ssRNA40. hTLR8ED is depicted in green while ssRNA 40 is in red. This figure was generated from PDB code 4R08 [27]. All the figures were generated from The Research Collaboratory for Structural Bioinformatics PDB website: http://www.rcsb.org/pdb/. [109].

Figure 2. TLR signalling pathways

TLRs signal through MyD88-dependent and MyD88-independent pathways.1) MyD88 signaling pathway. After ligand binding at the plasma membrane (TLR2/1, TLR2/6, TLR4/MD-2 and TLR5) or endocytic vesicles (TLR7, TLR8, TLR9), TLRs recruit the adaptor molecule MyD88 to their TIR domains. TLR2/1, TLR2/6, TLR4/MD-2 also recruit the MyD88 adapter like protein (MAL) or also called TIR domain-containing adaptor protein (TIRAP). MyD88 consists of two domains: a TIR domain, which interacts with the TIR domain of toll-like receptors and a death domain. The death domain of MyD88 recruits IRAK proteins 1, 2, 4, which recruit TRAF6 to the receptor complex. Phosphorylated IRAK1 and TRAF6 then dissociate from the receptor and form a complex with TAK1, TAB1 and TAB2 at the plasma membrane, which induces the phosphorylation of TAB2 and TAK1.Following TAK1 and TAB1 phosphorylation, IRAK1 is degraded at the plasma membrane, and the remaining complex (consisting of TRAF6, TAK1, TAB1 and TAB2) translocate to the cytosol leading to the ubiquitination of TRAF6, and activation of TAK1. Activated TAK1 modulates the IκB kinase (IKK) complex, which is composed of two kinase subunits (IKKα and IKKβ) and a regulatory subunit termed IKKγ or NEMO (NFκB essential modulator). In resting cells, IκB is bound to NFκB avoiding the translocation of NFκB to the nucleus. Activation of IKK leads to phosphorylation of IκBs, which trigger their polyubiquitination and proteosomal degradation and subsequently, releasing NFκB to translocate to the nucleus. AK1 also activates the MAP kinase kinase MKK3/6-p38 signaling cascade, leading to cAMP response element binding (CREB) nuclear transcription factor activation and the MKK4/7-Jun N-terminal kinase (JNK) mediated activation of the transcription factor activator protein-1 (AP-1). AP-1 in concert with NFκB activates the expression of pro-inflammatory cytokines, chemokines and MHC costimulatory molecules. 2) TRIF signaling pathway. After activation of TLR4 and TLR3, TRIF are recruited to their TIR domains. TRAM (TRIF-adaptor molecule) is another adaptor recruited to the TIR domain of TLR4. Subsequently IKKε (also known as inducible IKK (IKKi) and TBK1 and TRAF3 are recruited to the TRIF/TIR or TRAM/TRIF/TIR complexes. TBK1 phosphorylates IRF3 and IRF7, which activate, in complex with p300 and CBP (CREB binding protein), the expression of interferon inducible genes, IP-10 and RANTES. TRIF can also bind TRAF6 and activate a late production of pro-inflammatory cytokines through NFκB activation.