FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4+ T Lymphocytes

Abstract

Background: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. Materials and Methods: Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. Results: In vivo experiments showed that FTY720 inhibited the recruitment of CD4 + lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1β, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose-and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. Conclusion: Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4 + T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells.

Molecular Pharmacology and Novel Potential Therapeutic Applications of Fingolimod

“…Consequently, S1P receptor modulators may have broader beneficial therapeutic effects worth considering. Indeed, preclinical surveys have found that fingolimod can halt the development of different models of RA by acting on the S1P signaling pathway ( Yoshida et al, 2016 ; Zhu et al, 2021 ), neuropsychiatric SLE ( Mike et al, 2018 ), and also ameliorate clinical and histological signs of psoriasiform dermatitis ( Okura et al, 2021 ). Fingolimod is considered a treatment to prevent diabetes development by preserving ß -cell mass ( Maki et al, 2005 ; Moon et al, 2013 ).…”

Deletion of sphingosine kinase 2 attenuates cigarette smoke-mediated chronic obstructive pulmonary disease-like symptoms by reducing lung inflammation

“…Consistently, we found that collagen deposition in small airways induced by CS was significantly suppressed by FTY720 treatment. Notably, FTY720 also inhibited the phosphorylation level of Nf-κB-p65 and rescued the CFTR activity [ 52 ]. Therefore, regulation of pulmonary immune microenvironment by antagonizing S1P might contribute to alleviation of inflammation and fibrosis after chronic CS exposure.…”

Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy

“…The authors suggested that greater presence of S1P within the TME of lung cancer may orchestrate tumorigenic immune responses [ 268 ]. However, this statement requires experimental confirmation, as the exact mechanisms (specific S1P targets) of this effect remain unclear and/or controversial [ 269 , 270 ]. Furthermore, in non-Hodgkin’s lymphoma, SphK1 silencing resulted in activation of NKs, associated with increased secretion of IL-2 and IFN-γ, which are downstream of the classical NF-κB pathway [ 271 ].…”