靶向 miR-223 可增强多发性硬化症患者髓系来源抑制细胞的抑制活性。
Targeting miR-223 enhances myeloid-derived suppressor cell suppressive activities in multiple sclerosis patients.
机构信息
Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, 85013, United States.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, United States; Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy.
出版信息
Mult Scler Relat Disord. 2023 Aug;76:104839. doi: 10.1016/j.msard.2023.104839. Epub 2023 Jun 18.
BACKGROUND
Multiple sclerosis (MS) is an incurable autoimmune inflammatory demyelinating disease of the central nervous system. Several MS medications can modify disease course through effects on adaptive immune cells, while drugs targeting innate immunity are under investigation. Myeloid-derived suppressor cells (MDSCs) which arise during chronic inflammation, are defined by their T-cell immunosuppressive functions. MiR-223 modulates myeloid cell maturation and expansion, including MDSCs.
METHODS
MDSCs isolated from healthy controls (HC) and people with MS (pwMS) were co-cultured with CD4+ T-cells to study their immunosuppressive activities in vitro. Cytokines and chemokines concentration were evaluated by Luminex assay in the serum of HC, pwMS, and other neuroinflammatory diseases and correlated with MDSC activities.
RESULTS
MDSC suppressive functions are dysregulated in pwMS compared to HC, which was reversed by glucocorticoids (GC). GC specifically downregulated miR-223 levels in MDSCs and increased the expression of STAT3. In vitro assay showed that miR-223 inhibition enhanced MDSC suppressive activity, STAT3 dependently. By multiple linear regression analysis, we demonstrated that MDSC phosphorylated STAT3 was correlated with serum GM-CSF in HC and pwMS.
CONCLUSIONS
These results suggest that miR-223 could be a therapeutic target for enhancing MDSC's suppressive activities as an alternative to GC.
背景
多发性硬化症（MS）是一种中枢神经系统的无法治愈的自身免疫性炎症性脱髓鞘疾病。有几种 MS 药物可以通过对适应性免疫细胞的作用来改变疾病进程，而针对固有免疫的药物正在研究中。髓源性抑制细胞（MDSCs）在慢性炎症中产生，其特征是其 T 细胞免疫抑制功能。miR-223 调节髓样细胞的成熟和扩增，包括 MDSCs。
方法
从健康对照者（HC）和多发性硬化症患者（pwMS）中分离出 MDSC，与 CD4+T 细胞共培养，以研究其在体外的免疫抑制活性。通过 Luminex 测定法评估 HC、pwMS 和其他神经炎症性疾病患者血清中的细胞因子和趋化因子浓度，并与 MDSC 活性相关联。
结果
与 HC 相比，pwMS 中的 MDSC 抑制功能失调，糖皮质激素（GC）可逆转这种失调。GC 特异性地下调 MDSC 中的 miR-223 水平，并增加 STAT3 的表达。体外实验表明，miR-223 抑制增强了 MDSC 的抑制活性，这是依赖于 STAT3 的。通过多元线性回归分析，我们证明了在 HC 和 pwMS 中，MDSC 磷酸化 STAT3 与血清 GM-CSF 相关。
结论
这些结果表明，miR-223 可以作为增强 MDSC 抑制活性的治疗靶点，作为 GC 的替代物。
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