Proinflammatory microglial activation impairs in vitro cortical tissue repair via zinc-dependent ADAM17 cleavage of the CSF-1 receptor.

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-10-10 DOI:10.1111/jnc.16239
Diego R Hernandez-Espinosa, Gabriela I Medina-Ruiz, Mia G Scrabis, Amantha Thathiah, Elias Aizenman
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Abstract

Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.

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促炎性小胶质细胞活化通过锌依赖的 ADAM17 裂解 CSF-1 受体损害体外皮质组织修复。
感染和随后的炎症过程会对创伤性脑损伤(TBI)患者的预后产生负面影响。创伤性脑损伤后的组织修复受到小胶质细胞的严格调控,根据神经免疫细胞的活化状态促进或阻止星形胶质细胞介导的修复过程。本研究采用体外机械损伤模型,在大鼠神经元和胶质细胞混合皮质培养物中研究了鲜为人知的促炎性小胶质细胞活化和星形胶质细胞介导的组织修复机制。我们假设,促炎激活会破坏小胶质细胞对集落刺激因子 1(CSF-1)的反应,而集落刺激因子 1 会刺激小胶质细胞的迁移和增殖,这两者对于星形胶质细胞介导的组织修复都至关重要。机械损伤后,用脂多糖(LPS)和γ干扰素(IFNγ)处理培养物以诱导促炎状态。免疫细胞化学和生化分析用于评估神经胶质修复情况。促炎激活显著阻碍了伤口闭合,通过锌依赖性崩解酶和金属蛋白酶 17(ADAM17)的上调降低了小胶质细胞的水平,导致 CSF-1 受体(CSF-1R)的裂解。事实上,药物抑制 ADAM17 能有效促进炎症期间伤口的闭合。此外,锌螯合阻止了ADAM17介导的CSF-1R裂解,并诱导了营养因子的释放,显著改善了组织的恢复。我们的研究结果有力地确定了 ADAM17 是 CSF-1R 介导的信号传导的主要调节因子,并建立了一种机制来定义促炎性小胶质细胞活化与损伤后组织修复之间的关联。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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