TLRs, future potential therapeutic targets for RA

Abstract

Toll like receptor (TLR)s have a central role in regulating innate immunity and in the last decade studies have begun to reveal their significance in potentiating autoimmune diseases such as rheumatoid arthritis (RA). Earlier investigations have highlighted the importance of TLR2 and TLR4 function in RA pathogenesis. In this review, we discuss the newer data that indicate roles for TLR5 and TLR7 in RA and its preclinical models. We evaluate the pathogenicity of TLRs in RA myeloid cells, synovial tissue fibroblasts, T cells, osteoclast progenitor cells and endothelial cells. These observations establish that ligation of TLRs can transform RA myeloid cells into M1 macrophages and that the inflammatory factors secreted from M1 and RA synovial tissue fibroblasts participate in TH-17 cell development. From the investigations conducted in RA preclinical models, we conclude that TLR-mediated inflammation can result in osteoclastic bone erosion by interconnecting the myeloid and TH-17 cell response to joint vascularization. In light of emerging unique aspects of TLR function, we summarize the novel approaches that are being tested to impair TLR activation in RA patients.

Review: Cell Death, Nucleic Acids, and Immunity

“…5). Note that cell surface expressed TLRs, particularly TLR4, have been implicated in rheumatic diseases such as RA and scleroderma where non-nucleic acid containing cell debris may act as ligands (see (60, 61). …”

Pain pathogenesis in rheumatoid arthritis—what have we learned from animal models?

“…Toll-like receptors (TLR) are activated by endogenous damage-associated molecular patterns (DAMPs) such as fragmented extracellular matrix components, HMGB1 and heat-shock proteins. Many DAMPs are increased in RA models [31,79,87,116] and TLRs are expressed on a number of cell types, including immune cells, glia, chondrocytes, synoviocytes, osteoclasts and sensory neurons [54,79,95].…”

Toll‐like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of autoimmunity?

“…In particular, in view of their proautoimmunity effects, the possibility to modulate the immune system with TLR7/9‐targeting compounds appears promising for mitigating autoimmune processes. Drugs targeting the two receptors are under preclinical and clinical evaluation for some autoimmune diseases, particularly SLE and RA . They include immune modulatory oligonucleotides (IMOs) and small molecular inhibitors (SMIs) (Table ).…”

“…Drugs targeting the two receptors are under preclin-ical and clinical evaluation for some autoimmune diseases, particularly SLE and RA. 11,69 They include immune modulatory oligonucleotides (IMOs) and small molecular inhibitors (SMIs) ( Table 3). Among IMOs, the TLR7/8/9 antagonist IMO-8400 and the TLR7/9 antagonist IMO-3100 showed efficacy in mouse models of SLE and RA and entered clinical trials.…”