Amlexanox attenuates experimental autoimmune encephalomyelitis by inhibiting dendritic cell maturation and reprogramming effector and regulatory T cell responses
Amlexanox attenuates experimental autoimmune encephalomyelitis by inhibiting dendritic cell maturation and reprogramming effector and regulatory T cell responses
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Amlexanox 通过抑制树突状细胞成熟、重编程效应器和调节性 T 细胞反应来减轻实验性自身免疫性脑脊髓炎
DOI：
10.1186/s12974-019-1438-z
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发表时间：
2019-03-01
影响因子：
9.3
通讯作者：
Guo, Li
中科院分区：
文献类型：
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作者：
Quan, Mo-Yuan;Song, Xiu-Juan;Guo, Li
背景Amlexanox (ALX) 是一种 TBK1 抑制剂，可以调节免疫反应并具有抗炎特性。为了探讨其在调节实验性自身免疫性脑脊髓炎（EAE）进展中的作用，我们研究了ALX对树突状细胞（DC）成熟以及效应和调节性T细胞（Treg）反应的影响。方法在体外培养骨髓源性DC（BMDC）并用ALX处理。检测了它们的增殖、成熟及其诱导 T 细胞反应的刺激功能。在体内，记录了不同组的EAE的发展。在疾病高峰期，使用HE、LFB和电子显微镜（EM）评估炎症和脱髓鞘情况。还检测了脾 DC 的成熟以及 CNS 和外周的 Th1/Th17/Treg 反应。为了进一步探讨 ALX 在 DC 成熟中的作用机制，分析了 TBK1、IRF3 和 AKT 的激活。结果我们的数据表明，ALX 显着抑制 BMDC 的增殖和成熟，其特征是 MHCII（共刺激分子）、IL12 和 IL-23 表达减少，以及形态学改变。 ALX 处理的 BMDC 的共培养抑制同种异体 T 细胞增殖和 MOG 特异性 T 细胞反应。在 EAE 小鼠中，ALX 通过减少脊髓中的炎症浸润和脱髓鞘，同时减少脾脏致病性 Th1 和 Th17 细胞的频率以及增加 Tregs 来显着减弱 EAE 的发展。此外，ALX治疗减少了中枢神经系统和脾脏中的Th1和Th17细胞因子，但增加了Treg细胞因子。值得注意的是，ALX 治疗降低了脾 DC 上 CD80 和 CD86 的频率和表达，并降低了 IL-12 和 IL-23 的分泌，进一步支持了脾 DC 成熟受损。此外，ALX 有效降低 BMDC 和脾 DC 中 IRF3 和 AKT 的磷酸化，这两者都是 TBK1 的底物并与 DC 成熟相关。结论 ALX 是一种 TBK1 抑制剂，通过抑制 DC 成熟和随后的致病性 Th1 和 Th17 反应来减轻 EAE 的发展，同时通过减弱 Treg 反应来增加 Treg 反应。 TBK1/AKT 和 TBK1/IRF3 信号传导。
BackgroundAmlexanox (ALX), a TBK1 inhibitor, can modulate immune responses and has anti-inflammatory properties. To investigate its role in regulating the progression of experimental autoimmune encephalomyelitis (EAE), we studied the effect of ALX on the maturation of dendritic cells (DCs) and the responses of effector and regulatory T cells (Tregs).MethodsIn vitro, bone marrow-derived DCs (BMDCs) were cultured and treated with ALX. Their proliferation, maturation, and their stimulatory function to induce T cells responses were detected. In vivo, the development of EAE from different groups was recorded. At the peak stage of disease, HE, LFB, and electronic microscope (EM) were used to evaluate inflammation and demyelination. Maturation of splenic DC and Th1/Th17/Treg response in the CNS and peripheral were also detected. To further explore the mechanism underlying the action of ALX in DC maturation, the activation of TBK1, IRF3, and AKT was analyzed.ResultsOur data indicated that ALX significantly inhibited the proliferation and maturation of BMDCs, characterized by the reduced MHCII, a co-stimulatory molecule, IL12, and IL-23 expression, along with morphological alterations. Co-culture of ALX-treated BMDCs inhibited allogeneic T cell proliferation and MOG-specific T cell response. In EAE mice, ALX significantly attenuated the EAE development by decreasing inflammatory infiltration and demyelination in the spinal cords, accompanied by reduced frequency of splenic pathogenic Th1 and Th17 cells and increased Tregs. Moreover, ALX treatment decreased Th1 and Th17 cytokines, but increased Treg cytokines in the CNS and spleen. Notably, ALX treatment reduced the frequency and expression of CD80 and CD86 on splenic DCs and lowered IL-12 and IL-23 secretion, further supporting an impaired maturation of splenic DCs. In addition, ALX potently reduced the phosphorylation of IRF3 and AKT in BMDC and splenic DCs, both of which are substrates of TBK1 and associated with DC maturation.ConclusionsALX, a TBK1 inhibitor, mitigated EAE development by inhibiting DC maturation and subsequent pathogenic Th1 and Th17 responses while increasing Treg responses through attenuating the TBK1/AKT and TBK1/IRF3 signaling.