Department of Physiology & Pharmacology (R.E., M.D.H.), Department of Medicine (R.E., M.D.H.), Department of Clinical Neurosciences (R.E., K.S.R., H.F.K.), Department of Biochemistry and Molecular Biology (B.W.E., R.M.Y.), Department of Comparative Biology and Experimental Medicine (B.W.E., R.M.Y.), and Department of Cell Biology and Anatomy (H.F.K.), Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran (R.E., F.N.).
Department of Physiology & Pharmacology (R.E., M.D.H.), Department of Medicine (R.E., M.D.H.), Department of Clinical Neurosciences (R.E., K.S.R., H.F.K.), Department of Biochemistry and Molecular Biology (B.W.E., R.M.Y.), Department of Comparative Biology and Experimental Medicine (B.W.E., R.M.Y.), and Department of Cell Biology and Anatomy (H.F.K.), Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran (R.E., F.N.)
J Pharmacol Exp Ther. 2024 Jan 2;388(1):12-22. doi: 10.1124/jpet.123.001685.
Proteinase-activated receptor-2 (PAR2), which modulates inflammatory responses, is elevated in the central nervous system in multiple sclerosis (MS) and in its murine model, experimental autoimmune encephalomyelitis (EAE). In PAR2-null mice, disease severity of EAE is markedly diminished. We therefore tested whether inhibiting PAR2 activation in vivo might be a viable strategy for the treatment of MS. Using the EAE model, we show that a PAR2 antagonist, the pepducin palmitoyl-RSSAMDENSEKKRKSAIK-amide (P2pal-18S), attenuates EAE progression by affecting immune cell function. P2pal-18S treatment markedly diminishes disease severity and reduces demyelination, as well as the infiltration of T-cells and macrophages into the central nervous system. Moreover, P2pal-18S decreases granulocyte-macrophage colony-stimulating factor (GM-CSF) production and T-cell activation in cultured splenocytes and prevents macrophage polarization in vitro. We conclude that PAR2 plays a key role in regulating neuroinflammation in EAE and that PAR2 antagonists represent promising therapeutic agents for treating MS and other neuroinflammatory diseases. SIGNIFICANCE STATEMENT: Proteinase-activated receptor-2 modulates inflammatory responses and is increased in multiple sclerosis lesions. We show that the proteinase-activated receptor-2 antagonist palmitoyl-RSSAMDENSEKKRKSAIK-amide reduces disease in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis by inhibiting T-cell and macrophage activation and infiltration into the central nervous system, making it a potential treatment for multiple sclerosis.
蛋白酶激活受体-2（PAR2）调节炎症反应，在多发性硬化症（MS）和其小鼠模型实验性自身免疫性脑脊髓炎（EAE）的中枢神经系统中升高。在 PAR2 缺失小鼠中，EAE 的疾病严重程度明显降低。因此，我们测试了体内抑制 PAR2 激活是否是治疗 MS 的可行策略。使用 EAE 模型，我们表明 PAR2 拮抗剂，即棕榈酰-RSSAMDENSEKKRKSAIK-酰胺（P2pal-18S）肽，通过影响免疫细胞功能来减轻 EAE 的进展。P2pal-18S 治疗显著减轻疾病严重程度，并减少脱髓鞘，以及 T 细胞和巨噬细胞浸润到中枢神经系统。此外，P2pal-18S 减少培养脾细胞中的粒细胞-巨噬细胞集落刺激因子（GM-CSF）产生和 T 细胞活化，并防止体外巨噬细胞极化。我们得出结论，PAR2 在调节 EAE 中的神经炎症中起关键作用，PAR2 拮抗剂是治疗 MS 和其他神经炎症性疾病的有前途的治疗剂。
蛋白酶激活受体-2 调节炎症反应，在多发性硬化症病变中增加。我们表明，蛋白酶激活受体-2 拮抗剂棕榈酰-RSSAMDENSEKKRKSAIK-酰胺通过抑制 T 细胞和巨噬细胞的激活和浸润到中枢神经系统来减少多发性硬化症的实验性自身免疫性脑脊髓炎模型中的疾病，使其成为多发性硬化症的潜在治疗方法。
