Ezetimibe ameliorates clinical symptoms in a mouse model of ankylosing spondylitis associated with suppression of Th17 differentiation

Abstract

Ankylosing spondylitis (AS) is a chronic inflammatory disease that causes spinal inflammation and fusion. Although the cause of AS is unknown, genetic factors (e.g., HLA-B27) and environmental factors (e.g., sex, age, and infection) increase the risk of AS. Current treatments for AS are to improve symptoms and suppress disease progression. There is no way to completely cure it. High blood cholesterol and lipid levels aggravate the symptoms of autoimmune diseases. We applied hyperlipidemia drugs ezetimibe and rosuvastatin to AS mice and to PBMCs from AS patients. Ezetimibe and rosuvastatin was administered for 11 weeks to AS model mice on the SKG background. Then, the tissues and cells of mice were performed using flow cytometry, computed tomography, immunohistochemistry, and immunofluorescence. Also, the normal mouse splenocytes were cultured in Th17 differentiation conditions for in vitro analysis such as flow cytometry, ELISA and RNA sequencing. The 10 AS patients’ PBMCs were treated with ezetimibe and rosuvastatin. The patients’ PBMC were analyzed by flow cytometry and ELISA for investigation of immune cell type modification. Ezetimibe caused substantial inhibition for AS. The present study showed that ezetimibe inhibits Th17 cell function, thereby slowing the progression of AS. It is well known that statins are more effective in reducing blood lipid concentrations than ezetimibe, however, our results that ezetimibe had a better anti-inflammatory effect than rosuvastatin in AS. This data suggests that ezetimibe has an independent anti-inflammatory effect independent of blood lipid reduction. To investigate whether ezetimibe has its anti-inflammatory effect through which signaling pathway, various in vitro experiments and RNA sequencing have proceeded. Here, this study suggests that ezetimibe can be an effective treatment for AS patients by inhibiting Th17 differentiation-related genes such as IL-23R and IL-1R. Thus, this study suggests that ezetimibe has therapeutic potential for AS through inhibition of Th17 differentiation and the production of pro-inflammatory cytokines.

Molecular mechanisms of AMPK/YAP/NLRP3 signaling pathway affecting the occurrence and development of ankylosing spondylitis

“…The images were reconstructed using software to produce cross-sectional images with a pixel size of 16 μm. [ 41 ].…”

Crosstalk between cholesterol metabolism and psoriatic inflammation

“…And ezetimibe reduces monocyte chemoattractant protein 1-induced monocyte migration ( 40 ). Furthermore, ezetimibe was found to lower the frequency of Th17 and Th1 cells in RA mice and humans, as well as suppress the differentiation of Th17 cells and the production of pro-inflammatory molecules such as IL-1, IL-17, IFN-γ, TNF-α, and IL-6, thereby slowing the progression of RA ( 41 ). It has been documented that NPC1L1 could be affected by immune cells.…”

Jianpi Qingre Tongluo Decoction exerted an anti-inflammatory effect on AS by inhibiting the NONHSAT227927.1/JAK2/STAT3 axis

“…Synovial hyperplasia and bone erosion are the characteristic features of many inflammatory joint disease including AS [ 4 ] Fibroblast-like synoviocytes (FLSs), a heterogenous cell population of the synovium, contribute actively to inflammatory responses and play a decisive role in the pathophysiological process of AS. FLSs secrete a variety of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) [ 5 ] and interleukin-6 (IL-6) to trigger and exacerbate inflammatory signaling cascades [ 6 , 7 ], leading to local inflammation and joint destruction [ 8 ]. At present, the main goals of AS management are to control inflammation, promote functional recovery, and reduce deformity [ 9 ].…”