TLRs, future potential therapeutic targets for RA

Abstract

Toll like receptors (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.

Keywords: Bone erosion; Inflammation; M1 macrophages; Rheumatoid arthritis (RA); TH-17 cells; Toll like receptors (TLR)s.

Figure 1. Schematic figure illustrating the mechanism by which harmful stimuli can potentially activate release of TLR endogenous ligand that triggers TLR mediated inflammatory joint damage

Harmful stimuli such as injury, infection, stress and hypoxia promote tissue and cell death. As a result, endogenous ligands are released into RA synovial fluid where they can bind directly to cells that express TLRs such as RA macrophages, synovial tissue fibroblasts and pre-osteoclasts or affect cell (endothelial cells and TH-17 cell) function indirectly through production of inflammatory factors. The combined direct and indirect effects of TLR ligation facilitate inflammation, angiogenesis, TH-17 cell polarization and osteoclastic bone erosion which ultimately sustains the vicious cycle of inflammatory bone destruction.

Figure 2. Cell surface and endosomally expressed TLRs point to potential therapeutic approaches targeting TLR mode of action

TLRs are classified into two groups based on their distribution and ligand selection. TLRs 1, 2, 4, 5 and 6 are expressed on the cell surface and recognize microbial components, whereas, endosomal TLRs 3, 7, 8 and 9 primarily detect nucleic acids. There are a number of strategies utilized to abrogate TLR driven inflammatory responses. These strategies include: 1) use of soluble decoy receptors or neutralizing antibodies that abolish the ligand and receptor binding, 2) suppressing the production of endogenous ligands or the TLR expression levels, 3) inhibiting the TLR linked downstream pathways and 4) inhibiting TLR expression in part through mi-RNAs.

Figure 3. Schematic figure illustrating the mechanism by which TLR ligands potentiate RA pathology

Ligation of TLR4, 5 and 7 can transform RA myeloid cells into M1 macrophages and as a result the inflammatory factors released from M1 and RA ST fibroblasts participate in TH-17 cell polarization. Ligation of TLR5 via flagellin or TLR5 natural ligands expressed in RA SF transforms RA myeloid cells into mature osteoclasts. RA osteoclastogenesis is exacerbated through joint neovascularization mediated directly through TLR5 ligation or indirectly via TH-17 driven angiogenesis.