Activating systemic inflammation with lipopolysaccharide drives microglia-mediated degradation of perineuronal nets after cervical spinal cord injury in female rats

IF 4.8 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2027-02-01 Epub Date: 2026-10-14 DOI:10.1016/j.expneurol.2026.116068

Jaison Cucarian, Ram Rakheja, Kale R. Scatterty, Edward Armstrong, Sydney Storvold, Antoinette T. Nguyen, Keith Fenrich, Joshua E. Burda, Steve Lacroix, Karim Fouad

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Abstract

Functional gains from rehabilitative motor training after spinal cord injury (SCI) depend on neuroplasticity, which naturally declines over time. We previously demonstrated that combining the pro-inflammatory compound lipopolysaccharide (LPS) with motor training reawakens neuroplasticity and enhances its therapeutic efficacy in chronic cervical SCI rats, though the underlying mechanisms remained unclear. Here, we investigated whether LPS-induced inflammation facilitates neuroplasticity by degrading perineuronal nets (PNNs), extracellular structures known to restrict recovery after SCI.

Adult female Lewis rats received a single intraperitoneal LPS injection (1.5 mg/kg) ten days post-cervical SCI. In the first experiment, five days post-injection, we observed significantly diminished PNN marker fluorescence around ventral horn motor neurons in spared, injury-reactive spinal cord regions. To determine the cellular mechanism, we conducted a second experiment in which we pharmacologically attenuated microglial activity using minocycline (35 mg/kg). Minocycline treatment successfully prevented the LPS-induced loss of PNN fluorescence, demonstrating that microglia actively mediate PNN breakdown.

Collectively, these findings provide a proof-of-concept mechanism by which inflammation influences neuroplasticity following central nervous system injury. Our observations support the growing recognition that inflammation, far from being exclusively detrimental, holds the capacity to contribute to healing after injury. By activating microglia to degrade PNNs, LPS-induced inflammation removes the structural barrier surrounding motor neurons, potentially priming them to be more responsive to the neuroplastic changes induced by rehabilitative motor training, providing a plausible explanation for our previously reported outcomes. This study highlights neuroimmune interactions as key regulators of neuroplasticity and the therapeutic efficacy of rehabilitative interventions in neurological disorders.

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雌性大鼠颈脊髓损伤后，脂多糖激活全身性炎症，驱动小胶质细胞介导的神经元周围网降解。

脊髓损伤（SCI）后康复性运动训练的功能增强依赖于神经可塑性，而神经可塑性会随着时间的推移而自然下降。我们之前的研究表明，将促炎化合物脂多糖（LPS）与运动训练相结合，可以重新唤醒慢性颈椎脊髓损伤大鼠的神经可塑性，并提高其治疗效果，尽管其潜在机制尚不清楚。在这里，我们研究了lps诱导的炎症是否通过降解神经周围网络（PNNs）来促进神经可塑性，PNNs是已知限制脊髓损伤后恢复的细胞外结构。成年雌性Lewis大鼠在颈椎损伤后10天接受单次腹腔注射LPS （1.5 mg/kg）。在第一个实验中，在注射后5天，我们观察到在未受损伤的脊髓区域，腹角运动神经元周围的PNN标记荧光明显减弱。为了确定细胞机制，我们进行了第二个实验，我们使用米诺环素（35 mg/kg）从药理学上减弱了小胶质细胞的活性。米诺环素治疗成功地阻止了lps诱导的PNN荧光丧失，表明小胶质细胞积极介导PNN破坏。总的来说，这些发现提供了炎症影响中枢神经系统损伤后神经可塑性的概念验证机制。我们的观察结果支持了越来越多的认识，即炎症远不是唯一有害的，它有能力促进损伤后的愈合。通过激活小胶质细胞来降解pnn， lps诱导的炎症消除了运动神经元周围的结构屏障，潜在地使它们对康复运动训练引起的神经可塑性变化更敏感，这为我们之前报道的结果提供了合理的解释。本研究强调了神经免疫相互作用作为神经可塑性的关键调节因子和神经系统疾病康复干预的治疗效果。

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.