α-Enolase Expressed on the Surfaces of Monocytes and Macrophages Induces Robust Synovial Inflammation in Rheumatoid Arthritis

Abstract

α-Enolase (ENO1) is a multifunctional glycolytic enzyme expressed abundantly in the cytosol. It has been implicated in autoimmune and inflammatory diseases. Serum Abs against ENO1 were reported in rheumatoid arthritis (RA). Cell-surface expression of ENO1 has been found to be increased rapidly in response to inflammatory stimuli, but its expression and function has not been reported in RA. In this study, we show that cell-surface expression of ENO1 is increased on monocytes and macrophages isolated from RA patients but not on those from osteoarthritis patients, and Ab against ENO1 can stimulate these cells to produce higher amounts of proinflammatory mediators, such as TNF-α, IL-1 α/β, IFN-γ, and PGE2 via p38 MAPK and NF-κB pathway. The frequency of ENO1-positive cells in synovial fluid mononuclear cells was higher than PBMCs. ENO1-positive cells were also found in the inflamed synovium from RA patients and arthritic ankle tissues of mice with collagen-induced arthritis. Taken together, these findings suggest that Abs against ENO1 present in RA sera may stimulate monocytes and macrophages expressing cell-surface ENO1 and contribute to production of proinflammatory mediators during the effector phase of synovial inflammation.

Anti-α-enolase antibody limits the invasion of myeloid-derived suppressor cells and attenuates their restraining effector T cell response

“…21 ENO1 is also expressed on the cell surface of activated monocytes and macrophages in inflamed tissues, such as synovial fluid in rheumatoid arthritis patients, 14 and we confirmed its expression on BM-generated MDSC as well. Due to the presence of anti-ENO1 auto-antibodies in mice vaccinated with ENO1-DNA, we hypothesized that these antibodies play a role in limiting myeloid suppressor cell infiltration into the tumor area.…”

“…13,14 Due to the role of ENO1 as a plasminogen receptor, crucial for inducing plasmin activation and extracellular matrix degradation, which represent early steps for cellular migration, here we assessed if the anti-ENO1 antibody affected MDSC adhesion, invasion and migration. We also evaluated how cytokine secretion, arginase activity and T cell suppression functions were modulated by anti-ENO1 treatment.…”

Treponema denticola enolase contributes to the production of antibodies against ENO1 but not to the progression of periodontitis

“…Gingival tissues with chronic periodontitis are heavily infiltrated with activated T cells, B cells, monocytes, and neutrophils [26]. The anti-ENO1/mEno1 antibodies produced by molecular mimicry would contribute to tissue destruction through the induction of TNFα from activated leukocytes and immune complex-mediated tissue injury [15,16]. Meanwhile, as shown in T. forsythia and Streptococcus pneumoniae , bacterial enolases have pathogenic potential because they facilitate bacterial invasion and induce inflammatory cytokine production in monocytes [27,28].…”

“…In RA patients, a substantial percentage of peripheral blood mononuclear cells and synovial fluid mononuclear cells express ENO1 on the surface [16]. Interaction between anti-ENO1 antibodies and ENO1-positive cells in peripheral blood may contribute to the elevated TNFα serum levels in RA patients [29,30], and the circulating TNFα may in turn contribute to periodontal destruction.…”

“…Inflammatory stimuli induce rapid translocation of ENO1 from the cytosol to the cell surface, and cell-surface ENO1 serves as a receptor and activator of plasminogen, which assists inflammatory cell infiltration [15]. In addition, stimulation of cell surface ENO1 with anti-ENO1 antibodies induces the robust production of inflammatory cytokines from mononuclear leukocytes [16]. A recent study showed that anti-ENO1 antibody titers are associated with the severity of periodontitis as well as RA disease activity in RA patients [17].…”