Targeting DAMP Activation of Toll-Like Receptors: Novel Pathways to Treat Rheumatoid Arthritis?

Abstract

Inflammation is a necessary response to infection and injury by which the invading pathogen and/or damaged cells are cleared. Under normal circumstances this is a tightly controlled and transient process. However, in conditions such as rheumatoid arthritis (RA) these regulatory mechanisms appear inactive or ineffective such that inflammation progresses unchecked. This results in the pain, swelling and bone and cartilage destruction that define this disease. The etiology of RA initiation is still uncertain, but increasing evidence points to a key role for the toll-like receptor (TLR) family in driving aberrant inflammation in the joint. TLRs were originally identified as receptors for exogenous pathogen associated molecular patterns (PAMPs) of bacterial, fungal or viral origin, which initiate inflammation in response to microbial infection. Perhaps of more interest in the context of RA however, is the role that these molecules play in the recognition of endogenous danger signals or DAMPs (damage associated molecular patterns). DAMPs are generated by both infection-induced and sterile tissue damage. They include a wide range of molecules including intracellular proteins such as high mobility group protein 1 (HMGB1), cell derived nucleic acids and extracellular matrix molecules such as tenascin-C and fibrinogen. High levels of DAMPs are present in both the RA synovium and in the peripheral circulation in RA patients. Accumulating evidence from both human studies and experimental animal models now suggests that these molecules may be critical to the persistence of the inflammatory state in RA. Moreover, targeting TLRs and their downstream signalling pathways is emerging as a potentially tractable means for treating a range of inflammatory conditions, including RA and its associated pathologies. Here we focus on the current literature that demonstrates a role for DAMPs in driving chronic inflammation in RA. We will discuss the mechanistic differences between PAMP and DAMP mediated activation of TLRs; and highlight how these data have already informed novel pathways to develop improved therapies for RA and how future therapeutic strategies may further evolve.