Skip to main content
. Author manuscript; available in PMC: 2020 Oct 14.
Published in final edited form as: Semin Immunopathol. 2019 Oct 14;41(5):583–594. doi: 10.1007/s00281-019-00762-3

Figure 1: TLRs are transmembrane receptors that facilitate inflammatory signaling in response to PAMPs and DAMPs.

Figure 1:

In humans, TLR1, 2, 4, 5 and 6 are found on the cell membrane, while TLR3, 7, 8, 9 are located in endosomes. TLR2 exists as a homodimer, and also as a heterodimer in complex with TLR1 or TLR6. Several DAMPs found in the osteoarthritic joint and discussed in this review can interact with the cell-surface TLRs, including extracellular matrix components (e.g., biglycan, fibronectin (Fn) fragments, and an aggrecan-derived peptide - Ag 32-mer), and molecules produced directly by cells under stress (e.g., HMGB1, S100A8/9). In addition, low levels of the TLR4 ligand lipopolysaccharide (LPS) are found in OA joint fluids. A number of co-receptors or co-factors can modify the nature of TLR/ligand interactions. These include the soluble co-factors LBP and MD2 which facilitate LPS/TLR4 signaling, the receptor CD44 which can modulate the response to TLR2/4 ligands, and CD14 which can modulate the strength/sensitivity of TLR signaling and is active both in membrane and soluble form. Signaling through cell-surface TLRs requires the cytoplasmic adaptor, MyD88, and results in activation of the transcription factor NFκB (black arrows), which in turn leads to production of many inflammatory cytokines, chemokines and proteases. The endosomal TLRs can activate both NFκB and Interferon-regulator factors (IRFs) which promote a type I interferon response (grey arrows). TLR3 signaling is independent of MyD88, but utilizes the adaptor TRIF to activate IRFs. TLR4 can activate MyD88-dependent signaling at the cell surface, and then is internalized to the endosomal compartment where it can activate TRIF-dependent pathways as well. Most findings regarding specific TLR/DAMP interactions in OA models have largely implicated TLR2 and TLR4. However, microbial products of the microbiome have been hypothesized to interact with TLR5, while self-nucleic acids may interact with endosomal TLRs. These potential DAMP/TLR interactions and their relevance to OA need further investigation.