Toll-like receptors in the pathogenesis of autoimmune diseases: recent and emerging translational developments

Abstract

Autoinflammatory diseases are defined as the loss of self-tolerance in which an inflammatory response to self-antigens occurs, which are a significant global burden. Toll-like receptors are key pattern recognition receptors, which integrate signals leading to the activation of transcription factors and ultimately proinflammatory cytokines. Recently, it has become apparent that these are at the nexus of autoinflammatory diseases making them viable and attractive drug targets. The aim of this review was to evaluate the role of innate immunity in autoinflammatory conditions alongside the role of negative regulation while suggesting possible therapeutic targets.

Keywords: arthritis; autoimmunity; danger signals; toll-like receptors.

Figure 1

Basic signaling of TLRs: upon ligation with their associated ligands (common ones are shown in red), TLRs form homo- or heterodimers. Notes: Following ligation, TIR domains engage with adaptor proteins. TLRs 1, 2, 5, 6, 7, 8, 9 signal via the TIR domain-containing adaptor protein MyD88, while TLR3 uses the TRIF. TLR4 can move from the plasma membrane in order to switch signaling from MyD88 to TRIF, with the use of TRAM. A complex cascade, involving molecules such as IRAK-1, results in the induction of key transcription factors such as NF-κB. ‘’?”, unknown. Abbreviations: dsRNA, double-stranded RNA; IFNβ, interferon-β; IL, interleukin; IRAK-1, IL-1R-associated kinases; IRF, interferon regulatory factor; LPS, lipopolysaccharide; NF-κB, nuclear factor kappa B; TIR, toll IL-1 resistance; ssRNA, single-stranded RNA; TLR, toll-like receptor; TRAM, TRIF-related adapt molecule; TRIF, TIR-domain-containing adaptor protein-inducing IFNβ.

Figure 2

Role of TLRs in RA joint damage: initial cellular damage causes the release of DAMPs that are upregulated during inflammation, possibly caused by PAMPs. Notes: Consequent TLR activation on cells residing in the synovium results in increased production of key inflammatory cytokines such as TNF-α and IL-1, which in turn can activate FLS, leading to increased MMPs. Increased MMPs lead to the loss of homeostasis between TIMPs and MMPs leading to increased destruction of ECM and cartilage, causing the release of DAMPs and activation of TLRs on FLS. Abbreviations: DAMPs, damage-associated molecular patterns; ECM, extracellular matrix; FLS, fibroblast-like synoviocytes; HMGB-1, high-mobility group box 1; IL, interleukin; INF, interferon; miRNA, microRNA; MMPs, matrix metalloproteinases; PAMPs, pathogenic-associated molecular patterns; RA, rheumatoid arthritis; TIMPs, tissue inhibitor of metalloproteinases; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α.

Figure 3

Basic role of TLRs in myositis: post tissue damage (eg, via infection or exercise), cells release DAMPs. Notes: These DAMPs ligate to TLRs on infiltrating cells such as macrophages and plasmacytoid cells. The ligation ultimately results in the secretion of proinflammatory molecules into the microenvironment. IL-1 binds to its receptor, IL-1R, and exerts its downstream effects, which lead to capillary loss and hypoxia. The damage to the cells caused by the cytokine, in turn, produces more DAMPs that can bind to the TLR and induce further inflammation and increase chemokine release in the muscle fibers. Recent murine models of myositis have shown the importance of TLR8, MyD88, and NF-κB in the development of myositis. Possible dysregulation of miRNA and long noncoding RNAs and altered inflammation resolution also contribute. Abbreviations: DAMPs, damage-associated molecular patterns; ECM, extracellular matrix; FLS, fibroblast-like synoviocytes; IL, interleukin; miRNA, microRNA; MMPs, matrix metalloproteinases; NF-kB, nuclear factor kappa B; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α.