Zengeler Kristine E, Hollis Ava, Deutsch Tyler C J, Samuels Joshua D, Ennerfelt Hannah, Moore Katelyn A, Steacy Eric J, Sabapathy Vikram, Sharma Rahul, Patel Manoj K, Lukens John R
Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
Immunity. 2025 Jun 10;58(6):1519-1535.e11. doi: 10.1016/j.immuni.2025.04.007. Epub 2025 May 2.
Emerging evidence indicates that a baseline level of controlled innate immune signaling is required to support proper brain function. However, little is known about the function of most innate immune pathways in homeostatic neurobiology. Here, we report a role for astrocyte-dependent inflammasome signaling in regulating hippocampal plasticity. Inflammasomes are multiprotein complexes that promote caspase-1-mediated interleukin (IL)-1 and IL-18 production in response to pathogens and tissue damage. We observed that inflammasome complex formation was regularly detected under homeostasis in hippocampal astrocytes and that its assembly is dynamically regulated in response to learning and regional activity. Conditional ablation of caspase-1 in astrocytes limited hyperexcitability in an acute seizure model and impacted hippocampal plasticity via modulation of synaptic protein density, neuronal activity, and perineuronal net coverage. Caspase-1 and IL-18 regulated hippocampal IL-33 production and related plasticity. These findings reveal a homeostatic function for astrocyte inflammasome activity in regulating hippocampal physiology in health and disease.
新出现的证据表明，需要一定水平的可控先天性免疫信号基线来支持正常的脑功能。然而，对于大多数先天性免疫途径在稳态神经生物学中的功能知之甚少。在此，我们报告了星形胶质细胞依赖性炎性小体信号在调节海马可塑性中的作用。炎性小体是多蛋白复合物，可响应病原体和组织损伤促进半胱天冬酶-1介导的白细胞介素（IL）-1和IL-18的产生。我们观察到，在海马星形胶质细胞的稳态下经常检测到炎性小体复合物的形成，并且其组装会根据学习和区域活动而动态调节。在急性癫痫模型中，星形胶质细胞中半胱天冬酶-1的条件性缺失限制了过度兴奋，并通过调节突触蛋白密度、神经元活动和神经元周围网覆盖来影响海马可塑性。半胱天冬酶-1和IL-18调节海马IL-33的产生及相关可塑性。这些发现揭示了星形胶质细胞炎性小体活性在健康和疾病状态下调节海马生理的稳态功能。
