Inhibition of TLR4 signalling to dampen joint inflammation in osteoarthritis

Abstract Local and systemic low-grade inflammation, mainly involving the innate immune system, plays an important role in the development of OA. A receptor playing a key role in initiation of this inflammation is the pattern-recognition receptor Toll-like receptor 4 (TLR4). In the joint, various ligands for TLR4, many of which are damage-associated molecular patterns (DAMPs), are present that can activate TLR4 signalling. This leads to the production of pro-inflammatory and catabolic mediators that cause joint damage. In this narrative review, we will first discuss the involvement of TLR4 ligands and signalling in OA. Furthermore, we will provide an overview of methods for inhibit, TLR4 signalling by RNA interference, neutralizing anti-TLR4 antibodies, small molecules and inhibitors targeting the TLR4 co-receptor MD2. Finally, we will focus on possible applications and challenges of these strategies in the dampening of inflammation in OA.