Combination Therapy of Mesenchymal Stromal Cells and Interleukin-4 Attenuates Rheumatoid Arthritis in a Collagen-Induced Murine Model

Abstract

Rheumatoid arthritis (RA) is a disease of the joints that causes decreased quality of life. Mesenchymal stromal cells (MSCs) have immunosuppressive properties, with possible use in the treatment of RA. Similarly, interleukin (IL)-4 has been shown as a potential RA treatment. However, their combination has not been explored before. Therefore, this study aimed to investigate the effect of a combination therapy of MSCs and IL-4 in the treatment of RA, using a murine collagen-induced arthritis (CIA) model. Arthritis was induced in Balb/c mice by two intradermal injections of type II collagen (CII), at days 0 and 21. CIA mice were randomly assigned to four groups; group I received an intravenous injection of mouse bone marrow-derived MSCs, while group II received an intraperitoneal injection of IL-4. Group III received a combined treatment of MSC and IL-4, while group IV served as a CIA diseased control group receiving phosphate buffer saline (PBS). A fifth group of healthy mice served as the normal healthy control. To assess changes induced by different treatments, levels of RA-associated inflammatory cytokines and biomarkers were measured in the serum, knee joints, and synovial tissue, using ELISA and Real Time-qPCR. Histopathological features of knee joints were analyzed for all groups. Results showed that combined MSC and IL-4 treatment alleviated signs of synovitis in CIA mice, reverting to the values of healthy controls. This was evident by the decrease in the levels of rheumatic factor (RF), C-reactive protein (CRP) and anti-nuclear antibodies (ANA) by 64, 80, and 71%, respectively, compared to the diseased group. Moreover, tumor necrosis factor-alpha (TNF- α) and monocyte chemoattractant protein-1 (MCP-1) levels decreased by 63 and 68%, respectively. Similarly, our gene expression data showed improvement in mice receiving combined therapy compared to other groups receiving single treatment, where cartilage oligomeric matrix protein (Comp), tissue inhibitor metalloproteinase-1 (Timp1), matrix metalloproteinase1 (Mmp-1), and IL-1 receptor (Il-1r) gene expression levels decreased by 75, 70, and 78%, respectively. Collectively, treatment with a combined therapy of MSC and IL-4 might have an efficient therapeutic effect on arthritis. Thus, further studies are needed to assess the potential of different MSC populations in conjugation with IL-4 in the treatment of experimental arthritis.

A New Peracetylated Oleuropein Derivative Ameliorates Joint Inflammation and Destruction in a Murine Collagen-Induced Arthritis Model via Activation of the Nrf-2/Ho-1 Antioxidant Pathway and Suppression of MAPKs and NF-κB Activation

“…Moreover, COMP, a specific serological marker which evaluates the articular cartilage degradation and its turnover, exerts an active role in inflammation. Increased plasma levels of COMP have been detected in the degenerating cartilage, synovial fluid and serum of patients with knee injuries and primary osteoarthritis (OA) and RA [35,36]. Among MMPs, MMP-3 has been reported to be the major enzymes produced by fibroblasts and macrophage cells in the synovium, and is responsible for the degradation of proteoglycan, various type of collagens and denatured type I and type II collagens, among others, besides its direct enzyme activity its activation is necessary for full activation of collagenases [17].…”

Assessment of the anti‐rheumatoid arthritis activity of Gastrodia elata (tian‐ma) and Radix aconitic lateralis preparata (fu‐zi) via network pharmacology and untargeted metabolomics analyses

“…RA is a common autoimmune disease which might be induced by virus infection, such as Kaposi sarcoma‐associated herpesvirus, 36,37 Epstein‐Barr virus 38,39 and human cytomegalovirus 40 . Our results of targets‐pathways analysis (Figure 8) indicated that the identified compounds from TF couplet were involved in control of inflammation, 41 apoptosis, vascular endothelial function 42 and other RA‐related processes 43‐45 . Signaling pathways such as PI3K/AKT/mammalian target of rapamycin/nuclear factor‐κB is involved in the modulation of autophagy, chondrocytes proliferation and apoptosis of the synovial fibroblasts, all of which are closely linked to RA 46‐50 .…”

“…40 Our results of targets-pathways analysis (Figure 8) indicated that the 42 and other RA-related processes. [43][44][45] Signaling pathways such as PI3K/AKT/ mammalian target of rapamycin/nuclear factor-κB is involved in the modulation of autophagy, chondrocytes proliferation and apoptosis of the synovial fibroblasts, all of which are closely linked to RA. [46][47][48][49][50] Pathways that reduce reactive oxygen production are also valuable for inflammatory regulation in the context of RA.…”

IPSE, a parasite-derived, host immunomodulatory infiltrin protein, alleviates resiniferatoxin-induced bladder pain

“…Intraperitoneal injection of recombinant mouse IL-4 is used for systemic delivery of this cytokine. 10 – 13 Recombinant mouse IL-4 was obtained from Peprotech Laboratories (Rocky Hill, NJ, USA). A subset of mice underwent i.p.…”