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.

Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/01/27/jimmunol.090335

SummaryInterferon Regulatory Factor 5 (IRF5) plays a major role in setting up an inflammatory macrophage phenotype, but the molecular basis of its transcriptional activity is not fully understood. In this study, we conduct a comprehensive genome-wide analysis of IRF5 recruitment in macrophages stimulated with bacterial lipopolysaccharide and discover that IRF5 binds to regulatory elements of highly transcribed genes. Analysis of protein:DNA microarrays demonstrates that IRF5 recognizes the canonical IRF-binding (interferon-stimulated response element [ISRE]) motif in vitro. However, IRF5 binding in vivo appears to rely on its interactions with other proteins. IRF5 binds to a noncanonical composite PU.1:ISRE motif, and its recruitment is aided by RelA. Global gene expression analysis in macrophages deficient in IRF5 and RelA highlights the direct role of the RelA:IRF5 cistrome in regulation of a subset of key inflammatory genes. We map the RelA:IRF5 interaction domain and suggest that interfering with it would offer selective targeting of macrophage inflammatory activities.

No abstract

No abstract