Perez Jean-Christophe, Poulen Gaetan, Cardoso Maida, Boukhaddaoui Hassan, Gazard Chloé Marie, Courtand Gilles, Bertrand Sandrine Sylvie, Gerber Yannick Nicolas, Perrin Florence Evelyne
MMDN, Univ. Montpellier, EPHE, INSERM, Montpellier, France.
UMR 5221, Univ. Montpellier, CNRS, Montpellier, France.
Glia. 2023 Dec;71(12):2782-2798. doi: 10.1002/glia.24451. Epub 2023 Aug 4.
Traumatic spinal cord injury (SCI) induces irreversible autonomic and sensory-motor impairments. A large number of patients exhibit chronic SCI and no curative treatment is currently available. Microglia are predominant immune players after SCI, they undergo highly dynamic processes, including proliferation and morphological modification. In a translational aim, we investigated whether microglia proliferation persists at chronic stage after spinal cord hemisection and whether a brief pharmacological treatment could modulate microglial responses. We first carried out a time course analysis of SCI-induced microglia proliferation associated with morphological analysis up to 84 days post-injury (dpi). Second, we analyzed outcomes on microglia of an oral administration of GW2580, a colony stimulating factor-1 receptor tyrosine kinase inhibitor reducing selectively microglia proliferation. After SCI, microglia proliferation remains elevated at 84 dpi. The percentage of proliferative microglia relative to proliferative cells increases over time reaching almost 50% at 84 dpi. Morphological modifications of microglia processes are observed up to 84 dpi and microglia cell body area is transiently increased up to 42 dpi. A transient post-injury GW2580-delivery at two chronic stages after SCI (42 and 84 dpi) reduces microglia proliferation and modifies microglial morphology evoking an overall limitation of secondary inflammation. Finally, transient GW2580-delivery at chronic stage after SCI modulates myelination processes. Together our study shows that there is a persistent microglia proliferation induced by SCI and that a pharmacological treatment at chronic stage after SCI modulates microglial responses. Thus, a transient oral GW2580-delivery at chronic stage after injury may provide a promising therapeutic strategy for chronic SCI patients.
创伤性脊髓损伤（SCI）会导致不可逆的自主神经和感觉运动功能障碍。大量患者患有慢性脊髓损伤，目前尚无治愈性治疗方法。小胶质细胞是脊髓损伤后主要的免疫细胞，它们经历高度动态的过程，包括增殖和形态改变。为了实现转化医学目标，我们研究了脊髓半切术后慢性期小胶质细胞增殖是否持续存在，以及短暂的药物治疗是否可以调节小胶质细胞反应。我们首先进行了脊髓损伤诱导的小胶质细胞增殖的时间进程分析，并结合形态学分析，直至损伤后84天（dpi）。其次，我们分析了口服GW2580（一种集落刺激因子-1受体酪氨酸激酶抑制剂，可选择性降低小胶质细胞增殖）对小胶质细胞的影响。脊髓损伤后，小胶质细胞增殖在84 dpi时仍保持升高。增殖性小胶质细胞相对于增殖细胞的百分比随时间增加，在84 dpi时达到近50%。在84 dpi时均观察到小胶质细胞突起的形态改变，并且小胶质细胞胞体面积在42 dpi时短暂增加。在脊髓损伤后的两个慢性阶段（42和84 dpi）进行短暂的损伤后GW2580给药，可减少小胶质细胞增殖并改变小胶质细胞形态，从而引发继发性炎症的总体限制。最后，脊髓损伤后慢性期的短暂GW2580给药可调节髓鞘形成过程。我们的研究共同表明，脊髓损伤会诱导小胶质细胞持续增殖，并且脊髓损伤后慢性期的药物治疗可调节小胶质细胞反应。因此，损伤后慢性期短暂口服GW2580可能为慢性脊髓损伤患者提供一种有前景的治疗策略。
