Heat Shock Protein 96 Is Elevated in Rheumatoid Arthritis and Activates Macrophages Primarily via TLR2 Signaling

Abstract

Macrophages are important mediators of chronic inflammation and are prominent in the synovial lining and sublining of patients with rheumatoid arthritis (RA). Recently, we demonstrated increased TLR2 and TLR4 expression and increased response to microbial TLR2 and TLR4 ligands in macrophages from the joints of RA. The current study characterized the expression of the 96-kDa heat shock glycoprotein (gp96) in the joints of RA and its role as an endogenous TLR ligand to promote innate immunity in RA. gp96 was increased in RA compared with osteoarthritis and arthritis-free control synovial tissues. The expression of gp96 strongly correlated with inflammation and synovial lining thickness. gp96 was increased in synovial fluid from the joints of RA compared with disease controls. Recombinant gp96 was a potent activator of macrophages and the activation was mediated primarily through TLR2 signaling. The cellular response to gp96 was significantly stronger with RA synovial macrophages compared with peripheral blood monocytes from RA or healthy controls. The transcription of TLR2, TNF-α, and IL-8, but not TLR4, was significantly induced by gp96, and the induction was significantly greater in purified RA synovial macrophages. The expression of TLR2, but not TLR4, on synovial fluid macrophages strongly correlated with the level of gp96 in the synovial fluid. The present study documents the potential role of gp96 as an endogenous TLR2 ligand in RA and provides insight into the mechanism by which gp96 promotes the chronic inflammation of RA, identifying gp96 as a potential new therapeutic target.

Porphyromonas gingivalis Stimulates Bone Resorption by Enhancing RANKL (Receptor Activator of NF-κB Ligand) through Activation of Toll-like Receptor 2 in Osteoblasts

“…Our findings provide an explanation of why P. gingivalis can stimulate alveolar bone loss but might also contribute to our understanding of why oral infection with P. gingivalis seems to cause a more severe loss of juxta-articular bone in RA. TLR2, which is highly expressed in RA synovium (50 -52), is not only activated by pathogen-associated molecular patterns such as P. gingivalis but also by endogenous ligands present in RA synovium such as gp96 (53) and Snapin (54). Our data may also help to explain the role of endogenous ligands in the pathogenesis of RA bone erosions.…”

Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

“…CD91 was initially identified as a gp96 receptor, but its actual contribution is controversial (44). More recent evidence suggests that gp96 binds instead to TLR2 (27). TLR2 is expressed in all T cells, including CD4 + (mainly Th17), CD8 + , and NKT cells, and, at higher levels, gd T cell populations.…”

“…When externalized, gp96 or its N terminus fragments eventually serve as endogenous ligands for TLR2 (27). Thus, we considered that extracellular calpains could affect the association of gp96 with lymphocyte plasma membrane by limiting its binding to TLR2.…”

Role Of Toll Like Receptors In Various Diseases

“…108,109 Bununla beraber RA hastalarının sinovyal dokularında fibrinojen, HSP 60, 70, EDA, GP 96, fibronektin gibi birçok potansiyel endojen TLR ligandlarının varlığı belirlenmiştir. 110 RA'de gelişen inflamasyona bağlı olarak sentezlenen ve salınan endojen TLR ligandları, hastalığın hasar verici ve kalıcı etkisiyle ilişkilendirilmiştir. SLE, B lenfosit hiperreaktivitesi ve otoantikor üretimiyle karakterize sistemik otoimmün bir hastalıktır.…”