Expression of heat shock protein receptors on fibroblast-like synovial cells derived from rheumatoid arthritis-affected joints

Abstract

We examined the membrane expression of inducible Hsp70 and HSP receptors like TLR2, TLR4, CD14, CD36, CD40 and CD91 on fibroblast-like synovial cells (SC) derived from synovial tissue in 23 patients with rheumatoid arthritis (RA), who underwent synovectomy by using flow cytometric analysis. For comparison, autologous skin fibroblasts (SF) derived from the operation wound were tested. Significantly higher Hsp70 expression was found on synovial cells than on skin fibroblasts (median SC 21.4% x SF 5.0%, P < 0.001). Both synovial cells and skin fibroblasts expressed high levels of cell surface CD91 (median SC 80.2% x SF 79.2%), however, no or low levels of CD14, CD40, TLR2, TLR4 and CD36. Further, we observed high co-expression of CD91 and Hsp70 on RA synovial cells (median 18.6%), while skin fibroblasts showed only background Hsp70 expression (median 3.9%, P < 0.001). Since we demonstrated the high prevalence of inducible Hsp70 in RA synovial fluids, we speculate that Hsp70 might be captured onto the membrane of synovial cells from the extracellular space via the CD91 receptor. The significance of the Hsp70 interaction with synovial cells via CD91 remains undefined, but may mediate other non-immune purposes.

Analysis of serum heat shock protein 70 (HSPA1A) concentrations for diagnosis and disease activity monitoring in patients with rheumatoid arthritis

“…Moreover, expression of HSPA1A is increased by inflammatory cytokines, such as TNF-α (Kang et al 2009). The resistance of synovial cells to stress is associated with the expression of HSPs in synovial tissues, which can protect cells from apoptotic death (Hromadnikova et al 2008;Nguyen et al 2006;Schett et al 1998). Although the anti-apoptotic role of HSPA1A has been demonstrated in a number of studies (Borges et al 2012), several other studies have shown that HSPA1A is expressed in RA synovial tissue (Sedlackova et al 2009) and knockdown of HSPA1A protects RA synoviocytes from stressinduced apoptosis via Akt signaling pathway (Kang et al 2009), which uphold the importance of HSPA1A role in RA pathogenesis and suggest that HSPA1A has dual functionality depending on its location, cell type, and stimulus type (Dybdahl et al 2002;De Maio 2011).…”

“…During the course of disease, activated Synovial cells produce proinflammatory molecules, which lead to joint destruction (Nguyen et al 2006). Such stress leads to the upregulation of HSP expression in synovial tissue, which protects synovial cells from apoptotic death and consequently prompts synovial cell growth and pannus formation (Hromadnikova et al 2008).…”

Extracellular heat shock protein 70 inhibits tumour necrosis factor-α induced proinflammatory mediator production in fibroblast-like synoviocytes

“…We speculate that HSP70 in medium may bind its specific surface receptor on the RA FLSs, and activate intracellular anti-inflammatory signal transduction pathways such as JAK2-STAT3-SOCS3, which can inhibit the TNF-α induced degradation of IκB as well as subsequent activation and nuclear translocation of NF-κB. Recently, Human RA FLSs were shown to express high levels of the CD91 molecule [ 51 ], which is a known internalizing receptor for HSP70. Therefore, it is also possible that HSP70 may interact with the cell surface via the CD91 receptor, leading to receptor mediated endocytosis.…”

Functional expression of the alpha 2-macroglobulin receptor CD91 in salivary gland epithelial cells

“…The regulation of CD91 expression in other inflammatory disorders remains elusive. Recent findings have shown high membrane CD91 expression on synovial tissue in rheumatoid arthritis [23], whereas it has been reported that CD91 þ -dendritic cells juxtaposed to keratinocytes expressing excess heat-shock proteins (HSPs) in psoriatic plaques [24]. In addition, up-regulated monocytic CD91 expression has been correlated with slow progression in melanoma patients [25], whereas low CD91 expression has been reported in long-term nonprogressing HIV-1-infected patients [26].…”