Businaro Rita, Corsi Mariangela, Azzara Gabriella, Di Raimo Tania, Laviola Giovanni, Romano Emilia, Ricci Lidia, Maccarrone Mauro, Aronica Eleonora, Fuso Andrea, Ricci Serafino
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100, Latina, Italy.
Section of Department of Cell Biology & Neuroscience, Section Behavioural Neuroscience, Istituto Superiore di Sanità, Roma, Italy.
J Neuroinflammation. 2016 Jan 5;13:2. doi: 10.1186/s12974-015-0466-6.
Autism spectrum disorder (ASD) is a neurodevelopmental disease which affects 1 in 88 children. Its etiology remains basically unknown, but it is apparent that neuroinflammation is involved in disease development. Great attention has been focused on pro-inflammatory cytokines, and several studies have reported their dysfunction unbalance in serum as well as in the brain. The present work aimed at evaluating putative dysregulation of interleukin-18 (IL-18), a pro-inflammatory cytokine of the IL-1 family in the sera of patients with ASD of different grades, compared to healthy controls, as well as in postmortem brain samples obtained from patients with tuberous sclerosis as well as acute inflammatory diseases. Moreover, quantitative analysis of IL-18 was performed in the sera and brain obtained from Reeler mice, an experimental model of autism.
Serum IL-18 levels were measured by ELISA. IL-18 was localized by immunohistochemical analysis in brain sections obtained from tuberous sclerosis and encephalitis patients, as well as from gender- and age-matched controls, and in the brain sections of both Reeler and wild-type mice. IL-18 was also quantified by Western blots in homogenates of Reeler and wild-type mice brains. IL-18 binding protein (IL-18BP) was evaluated in Reeler and wild-type mice plasma as well as in their brains (sections and homogenates).
IL-18 content decreased in the sera of patients with autism compared to healthy subjects and in Reeler sera compared to wild-type controls. IL-18 was detected within glial cells and neurons in the brain of subjects affected by tuberous sclerosis and encephalitis whereas in healthy subjects, only a weak IL-18 positivity was detected at the level of glial cells. Western blot identified higher amounts of IL-18 in Reeler brain homogenates compared to wild-type littermates. IL-18BP was expressed in higher amounts in Reeler brain compared to the brain of wild-type mice, whereas no significant difference was detected comparing IL-18BP plasma levels.
IL-18 is dysregulated in ASD patients. Further studies seemed necessary to clarify the molecular details behind IL-18 increase in the brain and IL-18 decrease in the sera of patients. An increase in the size of the patient cohort seems necessary to ascertain whether decreased IL-18 content in the sera can become a predictive biomarker of ASD and whether its measure, in combination with other markers (e.g., increased levels of brain-derived neurotrophic factor (BDNF)), may be included in a diagnostic panel.
自闭症谱系障碍（ASD）是一种神经发育疾病，每88名儿童中就有1人受其影响。其病因基本上仍不明确，但神经炎症显然参与了疾病的发展。促炎细胞因子已受到高度关注，多项研究报告了它们在血清和大脑中的功能失调失衡情况。本研究旨在评估白细胞介素-18（IL-18）的假定失调情况，IL-18是IL-1家族的一种促炎细胞因子，在不同程度的ASD患者血清中与健康对照进行比较，以及在结节性硬化症患者和急性炎症性疾病患者的死后脑样本中进行评估。此外，还对自闭症实验模型Reeler小鼠的血清和大脑中的IL-18进行了定量分析。
通过酶联免疫吸附测定（ELISA）测量血清IL-18水平。通过免疫组织化学分析在结节性硬化症和脑炎患者以及性别和年龄匹配的对照的脑切片中，以及在Reeler小鼠和野生型小鼠的脑切片中定位IL-18。还通过蛋白质免疫印迹法对Reeler小鼠和野生型小鼠脑匀浆中的IL-18进行定量。在Reeler小鼠和野生型小鼠的血浆及其大脑（切片和匀浆）中评估IL-18结合蛋白（IL-18BP）。
与健康受试者相比，自闭症患者血清中的IL-18含量降低，与野生型对照相比，Reeler小鼠血清中的IL-18含量也降低。在结节性硬化症和脑炎患者的大脑中的神经胶质细胞和神经元内检测到IL-18，而在健康受试者中，仅在神经胶质细胞水平检测到弱阳性的IL-18。蛋白质免疫印迹法显示，与野生型同窝小鼠相比，Reeler小鼠脑匀浆中的IL-18含量更高。与野生型小鼠的大脑相比，Reeler小鼠大脑中IL-18BP的表达量更高，而比较IL-18BP血浆水平时未检测到显著差异。
ASD患者中IL-18失调。似乎有必要进行进一步研究以阐明患者大脑中IL-18升高和血清中IL-18降低背后的分子细节。似乎有必要增加患者队列的规模，以确定血清中IL-18含量降低是否可成为ASD的预测生物标志物，以及其测量值与其他标志物（例如，脑源性神经营养因子（BDNF）水平升高）联合使用时是否可纳入诊断指标体系。
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