Abstract
Rheumatoid arthritis (RA) is a long-lasting intractable autoimmune disorder, which has become a substantial public health problem. Despite widespread use of biologic drugs, there have been uncertainties in efficacy and long-term safety. Mesenchymal stem cells (MSCs) have been suggested as a promising alternative for the treatment of RA because of their immunomodulatory properties. However, the precise mechanisms of MSCs on RA-related immune cells are not fully elucidated. The aim of this study was to investigate the therapeutic potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) as a new therapeutic strategy for patients with RA and to explore the mechanisms underlying hUCB-MSC-mediated immunomodulation. Mice with collagen-induced arthritis (CIA) were administered with hUCB-MSCs after the onset of disease, and therapeutic efficacy was assessed. Systemic delivery of hUCB-MSCs significantly ameliorated the severity of CIA to a similar extent observed in the etanercept-treated group. hUCB-MSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hUCB-MSCs on macrophages, macrophages were co-cultured with hUCB-MSCs. The tumor necrosis factor (TNF)-α-mediated activation of cyclooxygenase-2 and TNF-stimulated gene/protein 6 in hUCB-MSCs polarized naive macrophages toward an M2 phenotype. In addition, hUCB-MSCs down-regulated the activation of nucleotide-binding domain and leucine-rich repeat pyrin 3 inflammasome via a paracrine loop of interleukin-1β signaling. These immune-balancing effects of hUCB-MSCs were reproducible in co-culture experiments using peripheral blood mononuclear cells from patients with active RA. hUCB-MSCs can simultaneously regulate multiple cytokine pathways in response to pro-inflammatory cytokines elevated in RA microenvironment, suggesting that treatment with hUCB-MSCs could be an attractive candidate for patients with treatment-refractory RA.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied by progressive synovitis, destructive arthropathy and systemic complications
As we showed the anti-inflammatory effect of hUCB-mesenchymal stem cells (MSCs) in experimental colitis and atopic dermatitis,[10,17] we sought to investigate the therapeutic efficacy of hUCBMSCs in collagen-induced arthritis (CIA)
Given that anti-TNF-α therapies provide clinical benefits for RA patients,[38] these findings suggest that hUCB-MSCs can serve as a promising substitute for current therapeutics
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease accompanied by progressive synovitis, destructive arthropathy and systemic complications. As tumor necrosis factor-alpha (TNF-α) has a principal role in the pathogenesis of RA, anti-TNF-α biologic agents have brought marked clinical achievement in RA patients.[3] interleukin (IL)-1 and IL-6 blockades have been introduced because these cytokines are reported to be involved in the pathogenesis of RA.[4] despite the widespread use of targeted therapies, up to 50% of patients with RA still fail to respond adequately These approaches may carry longterm side effects, including serious infections and malignancies.[5,6] there are clear unmet demands to develop safe and effective therapeutics without the potential risk of complications. Targeting NLRP3 inflammasomes or their downstream pathways can be an effective strategy for attenuating RA
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