Microglial IKKβ Alters Central and Peripheral Immune Activity at Distinct Time Points After Spinal Cord Injury

IF 5.1 2区 医学 Q1 NEUROSCIENCES
Glia Pub Date : 2025-05-10 DOI:10.1002/glia.70030
Micaela L. O'Reilly, Mariah J. Wulf, Theresa M. Connors, Ying Jin, Frank Bearoff, Julien Bouyer, Sandhya Kortagere, John R. Bethea, Veronica J. Tom
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Abstract

After high-level spinal cord injury (SCI), persistently reactive microglia drive widespread plasticity throughout the neuraxis. Plasticity in the thoracolumbar cord, a region corresponding to the spinal sympathetic reflex (SSR) circuit, contributes to the development of sympathetic dysfunction and associated immune disorders. The transcription factor NF-κB is activated after SCI, promoting a pro-inflammatory loop by driving the expression of inflammatory mediators which further activate NF-κB signaling. We hypothesize that microglial NF-κB signaling via IKKβ modulates microglial activity, impacting central and peripheral immune activity related to the SSR circuit post-SCI. We assessed the effect of deleting canonical IKKβ in CNS-resident microglia, its impact on microglial activation, polarization, central transcriptional activity, and peripheral immune activity at 1- and 4-week post-SCI (wpi). Transcriptomic analyses reveal microglial IKKβ influences immune-related pathways in the thoracolumbar cord at 1 wpi. We show that inhibition of microglial NF-κB signaling via deletion of the activator IKKβ mitigates injury-induced increases in “proinflammatory” M1 microglia in the thoracolumbar cord at 4 wpi and increases the quantity of splenocytes at 1 wpi. This study advances our understanding of how microglial IKKβ signaling shapes the neuroimmune response and a peripheral immune organ after SCI.

Abstract Image

小胶质细胞IKKβ在脊髓损伤后不同时间点改变中枢和外周免疫活性
高水平脊髓损伤(SCI)后,持续反应性小胶质细胞驱动整个神经轴广泛的可塑性。胸腰束的可塑性是一个与脊髓交感反射(SSR)回路相对应的区域,有助于交感功能障碍和相关免疫疾病的发展。转录因子NF-κB在脊髓损伤后被激活,通过驱动炎症介质的表达促进促炎循环,炎症介质进一步激活NF-κB信号传导。我们假设小胶质细胞NF-κB信号通过IKKβ调节小胶质细胞活性,影响与sci后SSR回路相关的中枢和外周免疫活性。在脊髓损伤后1周和4周,我们评估了在中枢神经系统驻留的小胶质细胞中删除典型IKKβ的效果,以及它对小胶质细胞激活、极化、中枢转录活性和外周免疫活性的影响。转录组学分析显示小胶质细胞IKKβ在1 wpi时影响胸腰束免疫相关通路。我们发现,通过删除激活因子IKKβ来抑制小胶质细胞NF-κB信号,可以减轻损伤诱导的胸腰束M1小胶质细胞的“促炎”增加,并增加脾细胞的数量。这项研究促进了我们对脊髓损伤后小胶质细胞IKKβ信号如何影响神经免疫反应和外周免疫器官的理解。
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来源期刊
Glia
Glia 医学-神经科学
CiteScore
13.10
自引率
4.80%
发文量
162
审稿时长
3-8 weeks
期刊介绍: GLIA is a peer-reviewed journal, which publishes articles dealing with all aspects of glial structure and function. This includes all aspects of glial cell biology in health and disease.
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