Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that was required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1-39 at the peak of EAE promoted disease remission. In vitro, CRAMP1-39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR)2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors (FFAR)2/3, and prevented EAE. This study shows that CRAMP produced by different cell types have opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.

中文翻译：

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Cathelicidin 抗菌肽在中性粒细胞和神经元中的表达拮抗调节神经炎症。


多发性硬化症 （MS） 是一种影响中枢神经系统 （CNS） 的自身免疫性疾病，其病理生理学尚不清楚，并且没有明确的治愈方法。抗菌肽 （AMP） 是在包括 CNS 在内的各种组织中表达的免疫调节分子。在这里，我们研究了 cathelicidin-related AMP （CRAMP） 是否调节实验性自身免疫性脑脊髓炎 （EAE）（一种 MS 小鼠模型）的发展。我们表明，在早期阶段，CNS 募集的中性粒细胞产生富含 CRAMP 的中性粒细胞胞外陷阱 （NET），这是 EAE 启动所必需的。NET 相关 CRAMP 刺激树突状细胞通过 cGAS/STING 通路产生 IL-6，从而促进产脑 Th17 反应。然而，在疾病后期，神经元也表达 CRAMP，从而降低了 EAE 的严重程度。神经元中的 Camp 敲低导致疾病恶化，而在 EAE 高峰期局部注射 CRAMP1-39 促进了疾病缓解。在体外，CRAMP1-39 通过甲酰肽受体 （FPR） 2 调节小胶质细胞和星形胶质细胞的激活。最后，丁酸盐（一种肠道微生物群衍生的代谢物）的给药通过游离脂肪酸受体 （FFAR）2/3 刺激神经 CRAMP 的表达，并阻止 EAE。这项研究表明，不同细胞类型产生的 CRAMP 对神经炎症具有相反的影响，为 MS 和其他神经炎症性疾病提供了治疗机会。