Molet Jenny, Mauborgne Annie, Diallo Mickael, Armand Vincent, Geny David, Villanueva Luis, Boucher Yves, Pohl Michel
Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris, France.
Université Paris Descartes, Paris, France.
J Neurochem. 2016 Jan;136(1):133-47. doi: 10.1111/jnc.13375. Epub 2015 Oct 28.
After peripheral nerve injury microglial reactivity change in the spinal cord is associated with an early activation of Janus kinase (JAK)/STAT3 transduction pathway whose blockade attenuates local inflammation and pain hypersensitivity. However, the consequences of microglial JAK/STAT3-mediated signaling on neighboring cells are unknown. Using an in vitro paradigm we assessed the impact of microglial JAK/STAT3 activity on functional characteristics of astrocytes and spinal cord neurons. Purified rat primary microglia was stimulated with JAK/STAT3 classical activator interleukin-6 in the presence or absence of a selective STAT3 inhibitor and rat primary astrocytes or spinal cord neurons were exposed to microglia conditioned media (CM). JAK/STAT3 activity-generated microglial CM modulated both astrocyte and neuron characteristics. Beyond inducing mRNA expression changes in various targets of interest in astrocytes and neurons, microglia CM activated c-Jun N-terminal kinase, STAT3 and NF-κB intracellular pathways in astrocytes and promoted their proliferation. Without modifying neuronal excitability or survival, CM affected the nerve processes morphology and distribution of the post-synaptic density protein 95, a marker of glutamatergic synaptic contacts. These findings show that JAK/STAT3 activity in microglia impacts the functional characteristics of astrocytes and neurons. This suggests its participation in spinal cord tissue plasticity and remodeling occurring after peripheral nerve injury. We show that the activity of JAK/STAT3 pathway in microglial cells confers them a specific signaling modality toward neighboring cells, promoting astrocyte proliferation and changes in neuronal morphology. These in vitro data suggest that the early JAK/STAT3 activation in spinal cord microglia, associated with peripheral nerve injury, participates in functional alteration of various cell populations and in spinal tissue remodeling.
外周神经损伤后，脊髓中的小胶质细胞反应性变化与Janus激酶（JAK）/信号转导和转录激活因子3（STAT3）转导通路的早期激活有关，阻断该通路可减轻局部炎症和疼痛超敏反应。然而，小胶质细胞JAK/STAT3介导的信号传导对邻近细胞的影响尚不清楚。我们使用体外模型评估了小胶质细胞JAK/STAT3活性对星形胶质细胞和脊髓神经元功能特性的影响。在存在或不存在选择性STAT3抑制剂的情况下，用JAK/STAT3经典激活剂白细胞介素-6刺激纯化的大鼠原代小胶质细胞，然后将大鼠原代星形胶质细胞或脊髓神经元暴露于小胶质细胞条件培养基（CM）中。JAK/STAT3活性产生的小胶质细胞CM调节了星形胶质细胞和神经元的特性。除了诱导星形胶质细胞和神经元中各种感兴趣靶标的mRNA表达变化外，小胶质细胞CM还激活了星形胶质细胞中的c-Jun氨基末端激酶、STAT3和核因子κB细胞内信号通路，并促进了它们的增殖。在不改变神经元兴奋性或存活率的情况下，CM影响了神经突起的形态以及突触后致密蛋白95（一种谷氨酸能突触接触的标志物）的分布。这些发现表明，小胶质细胞中的JAK/STAT3活性会影响星形胶质细胞和神经元的功能特性。这表明它参与了外周神经损伤后脊髓组织的可塑性和重塑。我们表明，小胶质细胞中JAK/STAT3通路的活性赋予它们一种针对邻近细胞的特定信号传导方式，促进星形胶质细胞增殖和神经元形态变化。这些体外数据表明，与外周神经损伤相关的脊髓小胶质细胞早期JAK/STAT3激活参与了各种细胞群的功能改变和脊髓组织重塑。
