Toll-like receptors and NOD-like receptors in rheumatic diseases

Abstract

The past 10 years have seen the description of families of receptors that drive proinflammatory cytokine production in infection and tissue injury. Two major classes have been examined in the context of inflammatory joint disease--the Toll-like receptors (TLRs) and NOD-like receptors (NLRs). TLRs such as TLR2 and TLR4 are being implicated in the pathology of rheumatoid arthritis, ankylosing spondylitis, lyme arthritis and osteoarthritis. Nalp3 has been identified as a key NLR for IL-1beta production and has been shown to have a particular role in gout. These findings present new therapeutic opportunities, possibly allowing for the replacement of biologics with small molecule inhibitors.

Figure 1

Signaling through pathogen-associated and damage-associated molecular patterns drives chronic inflammation in diseases like rheumatoid arthritis. Bacterial DNA, peptidoglycans, muramyl dipeptide and viral molecules have been found in arthritic joints. These microbial pathogen-associated molecular patterns (PAMPs) can drive inflammation through the membrane-bound (Toll-like receptor (TLR)) and cytosolic (NOD-like receptor (NLR)) pattern recognition receptors (PRRs). The resulting release in inflammatory cytokines can drive the damage of host tissue releasing damage-associated molecular patterns (DAMPs), such as high-mobility group box protein 1, GP96, heat shock proteins and ATP, which also activate both types of PRR resulting in a vicious cycle of inflammation.

Figure 2

Treating spontaneous arthritis with a TLR4 antagonist suppresses the clinical and histological characteristics of arthritis. Abdollahi-Roodsaz and colleagues have recently shown that treating collagen-induced arthritis (left-hand side) with a TLR4 antagonist suppresses the clinical and histological characteristics of arthritis (right-hand side). Histological images of knee joints are shown, stained with hematoxylin and eosin. Arrow indicates inflammatory cell influx and chondrocyte cell death. Image taken from [21]. Reproduced with permission of John Wiley and Sons.