Lipopolysaccharide Challenge Reveals Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Murine Systemic Lupus Erythematosus.
Lipopolysaccharide Challenge Reveals Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Murine Systemic Lupus Erythematosus.
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DOI：
10.3390/brainsci8100184
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发表时间：
2018-10-04
期刊：
影响因子：
3.3
通讯作者：
Mathis KW
中科院分区：
文献类型：
--
作者：
Pham GS;Mathis KW
系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，表现为自主神经功能障碍和异常炎症，脑和先天免疫系统之间的相互作用可能失调。下丘脑-垂体-肾上腺（HPA）轴是一条内源性神经-内分泌-免疫通路，通过激活迷走神经传入神经调节炎症反应。我们假设SLE的慢性炎症过程部分是由于HPA轴功能障碍，在传入迷走神经-室旁核（PVN）界面、垂体前叶和/或肾上腺水平。为了研究这一点，我们用脂多糖（LPS）攻击雌性对照和SLE小鼠，并测量c-Fos表达作为神经元活化的指标，血浆促肾上腺皮质激素（ACTH）作为垂体前叶功能的指标，血浆皮质酮作为肾上腺功能的指标。我们发现，c-Fos在PVN的表达，血浆促肾上腺皮质激素和皮质酮之间的未激发的SLE和对照组小鼠是可比的。PVN c-Fos增加相似的对照组和SLE小鼠LPS攻击后3小时，然而，有没有变化，血浆ACTH之间的任何实验组炎症后的挑战。血浆皮质酮显着增加LPS激发的SLE小鼠相比，他们的车辆治疗的同行，但在对照组。特别是，LPS攻击后，尽管血浆皮质酮升高，但LPS攻击的SLE小鼠脑和脾TNF-α升高。这表明，尽管在LPS攻击后PVN中正常的c-Fos表达和HPA轴的激活，但这种累积反应可能不足以保护SLE小鼠免受炎症刺激，导致异常升高的先天免疫反应和外周炎症。
Crosstalk between the brain and innate immune system may be dysregulated in systemic lupus erythematosus (SLE), a chronic autoimmune disease that presents with dysautonomia and aberrant inflammation. The hypothalamic-pituitary-adrenal (HPA) axis is an endogenous neuro-endocrine-immune pathway that can regulate inflammation following activation of vagal afferents. We hypothesized that chronic inflammatory processes in SLE are in part due to HPA axis dysfunction, at the level of either the afferent vagal-paraventricular nuclei (PVN) interface, the anterior pituitary, and/or at the adrenal glands. To study this, we challenged female control and SLE mice with lipopolysaccharide (LPS) and measured c-Fos expression as an index of neuronal activation, plasma adrenocorticotrophic hormone (ACTH) as an index of anterior pituitary function, and plasma corticosterone as an index of adrenal function. We found that c-Fos expression in the PVN, and plasma ACTH and corticosterone were comparable between unchallenged SLE and control mice. PVN c-Fos was increased similarly in control and SLE mice three hours after LPS challenge; however, there were no changes in plasma ACTH amongst any experimental groups post inflammatory challenge. Plasma corticosterone was markedly increased in LPS-challenged SLE mice compared to their vehicle-treated counterparts, but not in controls. Paradoxically, following LPS challenge, brain and spleen TNF-α were elevated in LPS-challenged SLE mice despite heightened plasma corticosterone. This suggests that, despite normal c-Fos expression in the PVN and activation of the HPA axis following LPS challenge, this cumulative response may not adequately defend SLE mice against inflammatory stimuli, leading to abnormally heightened innate immune responses and peripheral inflammation.
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DOI：
10.1016/s0889-8529(01)00004-4
发表时间：
2002-03-01
影响因子：
4.5
作者：
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通讯作者：
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影响因子：
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