Department of Integrative Immunobiology, Duke University, Durham, NC 27705, USA; Marcus Center for Cellular Cures, Duke University, Durham, NC 27705, USA.
Marcus Center for Cellular Cures, Duke University, Durham, NC 27705, USA.
J Neuroimmunol. 2023 Sep 15;382:578168. doi: 10.1016/j.jneuroim.2023.578168. Epub 2023 Aug 2.
Neurons require physiological IFN-γ signaling to maintain central nervous system (CNS) homeostasis, however, pathological IFN-γ signaling can cause CNS pathologies. The downstream signaling mechanisms that cause these drastically different outcomes in neurons has not been well studied. We hypothesized that different levels of IFN-γ signaling in neurons results in differential activation of its downstream transcription factor, signal transducer and activator of transduction 1 (STAT1), causing varying outcomes. Using primary cortical neurons, we showed that physiological IFN-γ elicited brief and transient STAT1 activation, whereas pathological IFN-γ induced prolonged STAT1 activation, which primed the pathway to be more responsive to a subsequent IFN-γ challenge. This is an IFN-γ specific response, as other IFNs and cytokines did not elicit such STAT1 activation nor priming in neurons. Additionally, we did not see the same effect in microglia or astrocytes, suggesting this non-canonical IFN-γ/STAT1 signaling is unique to neurons. Prolonged STAT1 activation was facilitated by continuous janus kinase (JAK) activity, even in the absence of IFN-γ. Finally, although IFN-γ initially induced a canonical IFN-γ transcriptional response in neurons, pathological levels of IFN-γ caused long-term changes in synaptic pathway transcripts. Overall, these findings suggest that IFN-γ signaling occurs via non-canonical mechanisms in neurons, and differential STAT1 activation may explain how neurons have both homeostatic and pathological responses to IFN-γ signaling.
神经元需要生理 IFN-γ 信号来维持中枢神经系统 (CNS) 的内稳态，然而，病理性 IFN-γ 信号会导致 CNS 病变。导致神经元产生截然不同结果的下游信号机制尚未得到很好的研究。我们假设神经元中不同水平的 IFN-γ 信号导致其下游转录因子信号转导和转录激活因子 1 (STAT1) 的不同程度激活，从而导致不同的结果。使用原代皮质神经元，我们表明生理 IFN-γ 引起短暂和短暂的 STAT1 激活，而病理性 IFN-γ 诱导持续的 STAT1 激活，从而使该途径对随后的 IFN-γ 挑战更敏感。这是 IFN-γ 的特异性反应，因为其他 IFNs 和细胞因子不会在神经元中引起这种 STAT1 激活或引发。此外，我们在小胶质细胞或星形胶质细胞中没有看到相同的效果，这表明这种非典型 IFN-γ/STAT1 信号在神经元中是独特的。持续的 Janus 激酶 (JAK) 活性促进了延长的 STAT1 激活，即使没有 IFN-γ 也是如此。最后，尽管 IFN-γ 最初在神经元中诱导了典型的 IFN-γ 转录反应，但病理性 IFN-γ 水平导致突触途径转录物的长期变化。总体而言，这些发现表明 IFN-γ 信号在神经元中通过非典型机制发生，并且差异 STAT1 激活可能解释了神经元如何对 IFN-γ 信号具有稳态和病理性反应。
