The role of toll-like receptors in rheumatoid arthritis

Abstract

An increasing body of data supports the role of the innate immune system in the pathogenesis of rheumatoid arthritis (RA). Toll-like receptors (TLRs) are expressed by cells within the RA joint and various endogenous TLR ligands are present within the inflamed joints of patients with RA. Further, various animal models suggest that TLR signaling is important in the pathogenesis of disease. Overall, the data suggest that activation by endogenous TLR ligands may contribute to the persistent expression of proinflammatory cytokines by macrophages and the joint damage to cartilage and bone that occurs in RA. The data support a potential role for suppression of TLR signaling as a novel therapeutic approach in patients with RA.

Figure 1. Overview of TLR signal pathway

Upon ligand binding, TLRs interact with its corresponding adaptors, which result in MyD88-dependent and MyD88-independent pathways. Each of the TLRs except TLR3 transmits signals through the MyD88-mediated pathway, which leads to the activation of NF-κB and MAPKs, resulting in the expression of pro-inflammatory cytokines and chemokines. Activation of TLR3 and TLR4 through the MyD88-independent pathway is mediated through TRIF, resulting in the expression of type I interferons, IFNα and β, and the delayed activation of NF-κB and MAPKs, which is mediated through TNFα. The activation of NF-κB also results in the induction of A20, which suppresses NF-κB activation.

Figure 2. Unifying hypothesis of endogenous TLR ligands in the pathogenesis of RA

The exposure of genetically susceptible individuals into initial environmental stimulus might result in the activation of the innate and adoptive immune systems followed by inflammation. Endogenous TLR ligands (such as gp96) are expressed and released as a result of the inflammation. Other components released may also serve as autoantigens resulting in the formation of both pathogenic immune complexes or endogenous TLR ligands, capable of inducing a self-perpetuating inflammatory process, driving the persistent expression of macrophage-related cytokines and chemokines, which play an important role in the pathogenesis of RA.