Modulation of the Innate Immune Response by NMDA Receptors Has Neuropathological Consequences
Modulation of the Innate Immune Response by NMDA Receptors Has Neuropathological Consequences
复制标题
NMDA 受体调节先天免疫反应具有神经病理学后果
作者：
I. Glezer;H. Zekki;C. Scavone;S. Rivest
本研究的目的是确定谷氨酸受体是否调节C3H/HeN和C3H/HeJ小鼠脑内的先天免疫反应；后者承担toll样受体（TLR） 4基因功能的丧失。小鼠接受肠内注射脂多糖（LPS）， TLR4的外源性配体，并在此后多次死亡。这种治疗激活了参与先天免疫反应控制的多种基因的转录。MK-801是一种NMDA谷氨酸受体亚型拮抗剂，可加重C3H/HeN小鼠脑内毒素的作用，但在tlr4缺失的动物中无此作用。MK-801与LPS联合作用后，C3H/HeN小鼠同侧不同时间TLR2、CD14、肿瘤坏死因子-α、抑制因子-κBα mRNA的杂交信号增强。C3H/HeN小鼠大脑中这种强烈的炎症反应与任何令人信服的神经退行性变或脱髓鞘迹象无关，这在注射后2周内通过多种方法得到了证实。然而，长期接受LPS和MK-801 IS输注的动物，表现出同侧脱髓鞘水平显著增加。我们的研究结果表明，谷氨酸与其同源的NMDA受体的结合以tlr4依赖的方式调节lps诱导的先天免疫反应。这种急性反应可能对消除细菌细胞壁成分和减少组织损伤至关重要。然而，持续解除涉及NMDA受体的促炎信号导致脱髓鞘，这可能是参与这种病理条件的机制。
The aim of this study was to determine whether glutamate receptors modulate the innate immune response in the brain of C3H/HeN and C3H/HeJ mice; the latter bear a loss of function in the toll-like receptor (TLR) 4 gene. Mice received an intrastriatal (IS) infusion of lipopolysaccharide (LPS), the exogenous ligand for TLR4, and were killed at several times thereafter. This treatment activated the transcription of a wide variety of genes involved in the control of the innate immune response. MK-801, an antagonist of NMDA glutamate receptor subtype, exacerbated the effects of the endotoxin in the brain of C3H/HeN mice but not in TLR4-deficient animals. The ipsilateral side of C3H/HeN mice exhibited stronger hybridization signals for the mRNA encoding TLR2, CD14, tumor necrosis factor-α, and inhibitory factor-κBα at various times after the treatment combining MK-801 and LPS. This robust inflammatory response in the brain of C3H/HeN mice was not associated with any convincing signs of neurodegeneration or demyelination that was verified via numerous approaches and at time up to 2 weeks after injection. However, animals that received long-term IS infusion of LPS, together with MK-801, exhibited a significant increase in demyelination levels within the ipsilateral side. Our results demonstrate that binding of glutamate to its cognate NMDA receptor modulates LPS-induced innate immune reaction in a TLR4-dependent manner. This acute response may be crucial to eliminate bacterial cell wall components and minimizing tissue injury. However, sustained deregulation of proinflammatory signaling involving NMDA receptors leads to demyelination and is likely to be a mechanism participating in such pathological conditions.
影响因子：
30.5
作者：
Vladimir Toshchakov;Bryan W. Jones;P. Perera;K. Thomas;M. J. Cody;Shuling Zhang;B. Williams;J. Major;T. Hamilton;M. Fenton;S. Vogel
通讯作者：
Vladimir Toshchakov;Bryan W. Jones;P. Perera;K. Thomas;M. J. Cody;Shuling Zhang;B. Williams;J. Major;T. Hamilton;M. Fenton;S. Vogel