The role of glucocorticoid signaling in immune cells during excitotoxicity.

兴奋性毒性期间糖皮质激素信号在免疫细胞中的作用。

• 批准号: 7790688
• 负责人: Shawn Sorrells
• 金额: $ 3.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790688
• 关键词: Acute; Adrenal Glands; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Brain; Cells; Cessation of life; Chronic; Cytokine Signaling; Endotoxins; Exposure to; Glucocorticoids; Hormones; Immune; Immune Targeting; Immune response; Immunosuppressive Agents; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Kainic Acid; Knock-out; Knockout Mice; Leukocytes; Measures; Microglia; Mineralocorticoid Receptor; Mus; Neurons; Nuclear Hormone Receptors; Peripheral; Production; Property; Rattus; Receptor Signaling; Role; Signal Transduction; Site; Stress; TNF gene; Testing; Tissues; Wild Type Mouse; Work; base; cell type; central nervous system injury; cytokine; design; excitotoxicity; granulocyte; injured; macrophage; receptor; receptor-mediated signaling; research study; transcription factor

DESCRIPTION (provided by applicant): Glucocorticoids (GCs) are hormones released from the adrenal glands during stress and are well known for their potent and pleiotropic anti-inflammatory effects. In the injured CNS, their anti-inflammatory properties could be beneficial in cases where excessive inflammation imperils neuron survival. It is therefore important to understand specifically how GCs affect the immune response in the brain, especially given emerging evidence that under some circumstances GCs do not decrease inflammation and can even augment aspects of the immune response during CMS injury. It is well established that acute GC exposure can augment localized inflammatory responses while longer-term GC exposure is immunosuppressive. However, chronic GC exposure was recently found to increase CMS infiltration of macrophages, granulocytes, and microglia to excitotoxic injury accompanied by elevated levels of the pro-inflammatory cytokines IL-1(i, TNF-a, and IL-6. Chronic GC exposure was also found to augment CMS signaling of these cytokines and the pro-inflammatory transcription factor NFicB from peripheral exposure to endotoxin. Given their well-known anti-inflammatory properties, it is surprising that GCs do not blunt, but instead increase these inflammatory responses. Based on these findings, it is possible that chronic exposure to GCs augments the inflammatory response in the injured CMS. Chronic GC exposure could elevate CNS inflammation by stimulating any of the GC receptor subtypes in any of the cells present in the CNS. Two different nuclear hormone receptors for GCs exist, namely the GC receptor (GR) and the mineralocorticoid receptor (MR). A GR antagonist blocks the GC-augmented CNS inflammation, implicating the GR in this phenomenon; however it is unclear which cell type(s) are acted on by GCs to cause these pro-inflammatory effects. The most likely neuro-immune targets of GCs are the resident microglia and the peripheral leukocytes that extravasate to the site of injury. Both of these cell types express GR and are instrumental in orchestrating immune responses to acute injury. This proposal is designed to measure immune cell-specific effects of GCs during kainic acid-induced excitotoxicity by using previously characterized leukocyte-specific, GR-knockout mice. We will test the hypothesis that GR signaling in leukocytes is necessary for their increased recruitment and activation. We will also determine whether GR signaling in these cells affects the likelihood of neuron survival. The following aims are proposed to determine which of the observed effects of chronic GCs on inflammation and neuron death can be explained by leukocyte cell-autonomous GR signaling:

描述（由申请人提供）：糖皮质激素（GC）是在应激期间从肾上腺释放的激素，并且众所周知其强效和多效性抗炎作用。在受损的中枢神经系统中，它们的抗炎特性在过度炎症危及神经元存活的情况下可能是有益的。因此，重要的是要具体了解GC如何影响大脑中的免疫反应，特别是考虑到新出现的证据表明，在某些情况下，GC不会减少炎症，甚至可以在CMS损伤期间增加免疫反应的各个方面。已经确定，急性GC暴露可增强局部炎症反应，而长期GC暴露具有免疫抑制作用。然而，最近发现慢性GC暴露增加了巨噬细胞、粒细胞和小胶质细胞的CMS浸润，从而导致兴奋性毒性损伤，伴随着促炎细胞因子IL-1 α、TNF-α和IL-6水平升高。还发现慢性GC暴露增加来自外周暴露于内毒素的这些细胞因子和促炎性转录因子NFicB的CMS信号传导。鉴于其众所周知的抗炎特性，令人惊讶的是，GC不会钝化，而是增加这些炎症反应。基于这些发现，有可能长期暴露于GC增强了受损CMS中的炎症反应。慢性GC暴露可通过刺激CNS中存在的任何细胞中的任何GC受体亚型而升高CNS炎症。GC存在两种不同的核激素受体，即GC受体（GR）和盐皮质激素受体（MR）。GR拮抗剂阻断GC增强的CNS炎症，表明GR参与了这种现象;然而，尚不清楚GC作用于哪种细胞类型以引起这些促炎作用。GC最可能的神经免疫靶点是驻留的小胶质细胞和渗出到损伤部位的外周白细胞。这两种细胞类型都表达GR，并有助于协调对急性损伤的免疫反应。该提议旨在通过使用先前表征的白细胞特异性GR敲除小鼠来测量在红藻氨酸诱导的兴奋性毒性期间GC的免疫细胞特异性作用。我们将测试的假设，GR信号在白细胞是必要的增加招聘和激活。我们还将确定这些细胞中的GR信号是否影响神经元存活的可能性。提出以下目的以确定慢性GC对炎症和神经元死亡的观察到的影响中的哪一个可以通过白细胞自主GR信号传导来解释：

项目成果

Glucocorticoid signaling in myeloid cells worsens acute CNS injury and inflammation.

• DOI: 10.1523/jneurosci.4705-12.2013
• 发表时间: 2013-05-01
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Sorrells SF;Caso JR;Munhoz CD;Hu CK;Tran KV;Miguel ZD;Chien BY;Sapolsky RM
• 通讯作者: Sapolsky RM

The stressed CNS: when glucocorticoids aggravate inflammation.

• DOI: 10.1016/j.neuron.2009.09.032
• 发表时间: 2009-10-15
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Sorrells SF;Caso JR;Munhoz CD;Sapolsky RM
• 通讯作者: Sapolsky RM

Glucocorticoids increase excitotoxic injury and inflammation in the hippocampus of adult male rats.

• DOI: 10.1159/000367849
• 发表时间: 2014
• 期刊: Neuroendocrinology
• 影响因子: 4.1
• 作者: Sorrells SF;Munhoz CD;Manley NC;Yen S;Sapolsky RM
• 通讯作者: Sapolsky RM