Shie Feng-Shiun, Montine Kathleen S, Breyer Richard M, Montine Thomas J
Department of Pathology, University of Washington, Seattle, Washington, USA.
Glia. 2005 Oct;52(1):70-7. doi: 10.1002/glia.20220.
Prostaglandin (PG) E(2) acts via four functionally antagonistic E-prostanoid (EP) receptors that are expressed on multiple cell types in the nervous system; these are designated EP1-4. We showed previously that EP2 null mice are protected from CD14-dependent neuronal damage in vivo following intracerebroventricular (ICV) injection of lipopolysaccharide (LPS). Clear interpretation of this neuroprotective outcome is limited because EP2 is expressed on glia and neurons. We tested the hypothesis that microglial EP2 is required for paracrine neurotoxicity following activation of innate immunity, using primary murine microglia and neuron co-cultures. We demonstrated that microglial EP2 was necessary for lipopolysaccharide (LPS)-activated microglia-mediated neurotoxicity, as well as induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). Genetic deletion of microglial iNOS, pharmacological suppression of COX-2 activity, or addition of exogenous superoxide dismutase (SOD) and catalase in the presence of EP2 also abolished neurotoxicity. This loss of paracrine neurotoxicity by EP2(-/-) microglia occurred in the absence of reduced cytokine levels. We conclude that microglial EP2 is critical to innate immunity-mediated paracrine damage to neurons involving COX-2 and iNOS. EP2 should be considered as a therapeutic target for suppression of microglial innate immunity-mediated damage in neurodegenerative diseases.
前列腺素（PG）E2通过四种功能上相互拮抗的E-前列腺素（EP）受体发挥作用，这些受体在神经系统的多种细胞类型上表达；它们被命名为EP1-4。我们之前表明，在脑室内（ICV）注射脂多糖（LPS）后，EP2基因敲除小鼠在体内可免受CD14依赖性神经元损伤。由于EP2在神经胶质细胞和神经元上均有表达，因此对这种神经保护结果的清晰解释受到限制。我们使用原代小鼠小胶质细胞和神经元共培养物，测试了以下假设：先天性免疫激活后，旁分泌神经毒性需要小胶质细胞EP2。我们证明，小胶质细胞EP2对于脂多糖（LPS）激活的小胶质细胞介导的神经毒性以及诱导型一氧化氮合酶（iNOS）和环氧化酶2（COX-2）的诱导是必需的。小胶质细胞iNOS的基因缺失、COX-2活性的药物抑制或在存在EP2的情况下添加外源性超氧化物歧化酶（SOD）和过氧化氢酶也消除了神经毒性。EP2基因敲除的小胶质细胞旁分泌神经毒性的丧失发生在细胞因子水平未降低的情况下。我们得出结论，小胶质细胞EP2对于先天性免疫介导的涉及COX-2和iNOS的神经元旁分泌损伤至关重要。EP2应被视为抑制神经退行性疾病中小胶质细胞先天性免疫介导损伤的治疗靶点。
