Schepers Melissa, Paes Dean, Tiane Assia, Rombaut Ben, Piccart Elisabeth, van Veggel Lieve, Gervois Pascal, Wolfs Esther, Lambrichts Ivo, Brullo Chiara, Bruno Olga, Fedele Ernesto, Ricciarelli Roberta, Ffrench-Constant Charles, Bechler Marie E, van Schaik Pauline, Baron Wia, Lefevere Evy, Wasner Kobi, Grünewald Anne, Verfaillie Catherine, Baeten Paulien, Broux Bieke, Wieringa Paul, Hellings Niels, Prickaerts Jos, Vanmierlo Tim
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands; University MS Center (UMSC) Hasselt-Pelt, Hasselt, Belgium.
Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium; Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands.
Brain Behav Immun. 2023 Mar;109:1-22. doi: 10.1016/j.bbi.2022.12.020. Epub 2022 Dec 28.
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients. Hence, there is an urgent need for the development of new therapeutic strategies either targeting the destructive immunological demyelination or boosting endogenous repair mechanisms. Using in vitro, ex vivo, and in vivo models, we demonstrate that selective inhibition of phosphodiesterase 4 (PDE4), a family of enzymes that hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), reduces inflammation and promotes myelin repair. More specifically, we segregated the myelination-promoting and anti-inflammatory effects into a PDE4D- and PDE4B-dependent process respectively. We show that inhibition of PDE4D boosts oligodendrocyte progenitor cells (OPC) differentiation and enhances (re)myelination of both murine OPCs and human iPSC-derived OPCs. In addition, PDE4D inhibition promotes in vivo remyelination in the cuprizone model, which is accompanied by improved spatial memory and reduced visual evoked potential latency times. We further identified that PDE4B-specific inhibition exerts anti-inflammatory effects since it lowers in vitro monocytic nitric oxide (NO) production and improves in vivo neurological scores during the early phase of experimental autoimmune encephalomyelitis (EAE). In contrast to the pan PDE4 inhibitor roflumilast, the therapeutic dose of both the PDE4B-specific inhibitor A33 and the PDE4D-specific inhibitor Gebr32a did not trigger emesis-like side effects in rodents. Finally, we report distinct PDE4D isoform expression patterns in human area postrema neurons and human oligodendroglia lineage cells. Using the CRISPR-Cas9 system, we confirmed that pde4d1/2 and pde4d6 are the key targets to induce OPC differentiation. Collectively, these data demonstrate that gene specific PDE4 inhibitors have potential as novel therapeutic agents for targeting the distinct disease processes of MS.
多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性自身免疫性疾病，其特征为局灶性炎性病变和显著的脱髓鞘。尽管目前可用的疗法在治疗疾病的初始阶段有效，但它们无法阻止或逆转疾病进展至慢性进展阶段。到目前为止，尚无针对进展型MS患者的诱导修复治疗方法。因此，迫切需要开发新的治疗策略，要么针对破坏性免疫性脱髓鞘，要么增强内源性修复机制。利用体外、离体和体内模型，我们证明选择性抑制磷酸二酯酶4（PDE4）（一类水解并使环磷酸腺苷（cAMP）失活的酶）可减轻炎症并促进髓鞘修复。更具体地说，我们分别将促进髓鞘形成和抗炎作用分离为依赖PDE4D和PDE4B的过程。我们表明，抑制PDE4D可促进少突胶质前体细胞（OPC）分化，并增强小鼠OPC和人诱导多能干细胞衍生的OPC的（再）髓鞘形成。此外，PDE4D抑制在铜螯合剂模型中促进体内髓鞘再生，这伴随着空间记忆改善和视觉诱发电位潜伏期缩短。我们进一步确定，PDE4B特异性抑制具有抗炎作用，因为它降低体外单核细胞一氧化氮（NO）生成，并在实验性自身免疫性脑脊髓炎（EAE）早期改善体内神经学评分。与泛PDE4抑制剂罗氟司特不同，PDE4B特异性抑制剂A33和PDE4D特异性抑制剂Gebr32a的治疗剂量在啮齿动物中未引发类似呕吐的副作用。最后，我们报告了人类最后区神经元和人类少突胶质细胞谱系细胞中不同的PDE4D同工型表达模式。使用CRISPR-Cas9系统，我们证实pde4d1/2和pde4d6是诱导OPC分化的关键靶点。总体而言，这些数据表明基因特异性PDE4抑制剂有潜力作为针对MS不同疾病过程的新型治疗药物。
