Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis.

RA is a debilitating disorder that manifests as chronic localized synovial and systemic inflammation leading to progressive joint destruction. Recent advances in the molecular basis of RA highlight the role of both the innate and adaptive immune system in disease pathogenesis. Specifically, data obtained from in vivo animal models and ex vivo human tissue explants models has confirmed the central role of Toll-like receptors (TLRs) in RA. TLRs are pattern recognition receptors (PRRs) that constitute one of the primary host defence mechanisms against infectious and non-infectious insult. This receptor family is activated by pathogen-associated molecular patterns (PAMPs) and by damage-associated molecular patterns (DAMPs). DAMPs are host-encoded proteins released during tissue injury and cell death that activate TLRs during sterile inflammation. DAMPs are also proposed to drive aberrant stimulation of TLRs in the RA joint resulting in increased expression of cytokines, chemokines and proteases, perpetuating a vicious inflammatory cycle that constitutes the hallmark chronic inflammation of RA. In this review, we discuss the signalling mechanisms of TLRs, the central function of TLRs in the pathogenesis of RA, the role of endogenous danger signals in driving TLR activation within the context of RA and the current preclinical and clinical strategies available to date in therapeutic targeting of TLRs in RA.