Background

Down syndrome (DS) is a disorder characterised by marked immune dysfunction, increased mortality from sepsis, chronic inflammation, increased oxidative stress, sleep disturbance and possibly abnormal endogenous melatonin levels. Melatonin has a myriad of immune functions, and we hypothesised that this therapeutic agent could modulate the innate immune system in this cohort.

Methods

We investigated neutrophil and monocyte function (CD11b, TLR4 expression by flow cytometry), genes involved in TLR signalling (MyD88, IRAK4, TRIF), the inflammasome (NLRP3, IL-1β), and circadian rhythm (BMAL, CLOCK, CRY) by qPCR, and inflammatory cytokines (IL-2, IL-6, IL-8, IL-18, IL-1β, TNF-α, IFN-γ, IL-10, IL-1ra, VEGF, Epo, GM-CSF) by enzyme-linked immunosorbent assay (ELISA) following immunomodulation with LPS endotoxin and melatonin. 47 children with DS and 23 age- and sex-matched controls were recruited.

Results

We demonstrated that melatonin has several significant effects by reducing CD11b and TLR4 expression, attenuating TLR signalling, genes involved in the inflammasome and has the potential to reduce LPS-induced inflammatory responses.

Conclusions

Immunomodulatory effects of melatonin were found in both paediatric cohorts with more marked effects in the children with DS. Melatonin mediates immune response through a wide array of mechanisms and this immunomodulator may buffer the inflammatory response by regulating pro and anti-inflammatory signalling.

Impact

• We highlight that melatonin mediates its immune response through a wide array of mechanisms, its effects appear to be dose dependant and children with Down syndrome may be more receptive to treatment with it.

• Immunomodulatory effects of melatonin were demonstrated with marked effects in the children with Down syndrome with a reduction of MyD88, IL-1ß and NLRP3 expression in whole-blood samples.

• Melatonin is a proposed anti-inflammatory agent with a well-established safety profile, that has the potential for mitigation of pro- and anti-inflammatory cytokines in paediatric Down syndrome cohorts, though further clinical trials are warranted.

中文翻译：

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褪黑激素作为唐氏综合症儿童的免疫调节剂

背景

唐氏综合症 (DS) 是一种以明显的免疫功能障碍、败血症死亡率增加、慢性炎症、氧化应激增加、睡眠障碍和可能的内源性褪黑激素水平异常为特征的疾病。褪黑激素具有多种免疫功能，我们假设这种治疗剂可以调节该人群的先天免疫系统。

方法

我们研究了中性粒细胞和单核细胞功能（通过流式细胞仪检测 CD11b、TLR4 表达）、参与 TLR 信号传导的基因（MyD88、IRAK4、TRIF）、炎性体（NLRP3、IL-1β）和昼夜节律（BMAL、CLOCK、CRY） qPCR 和炎症细胞因子（IL-2、IL-6、IL-8、IL-18、IL-1β、TNF-α、IFN-γ、IL-10、IL-1ra、VEGF、Epo、GM-CSF）在用 LPS 内毒素和褪黑激素进行免疫调节后，通过酶联免疫吸附测定 (ELISA)。招募了 47 名 DS 儿童和 23 名年龄和性别匹配的对照。

结果

我们证明褪黑激素通过降低 CD11b 和 TLR4 表达、减弱 TLR 信号传导、参与炎性体的基因具有多种显着作用，并有可能减少 LPS 诱导的炎症反应。

结论

在两个儿科队列中都发现了褪黑激素的免疫调节作用，对 DS 患儿的影响更为显着。褪黑激素通过多种机制介导免疫反应，这种免疫调节剂可以通过调节促炎和抗炎信号传导来缓冲炎症反应。

影响

• 我们强调褪黑激素通过多种机制介导其免疫反应，其作用似乎具有剂量依赖性，患有唐氏综合症的儿童可能更容易接受它的治疗。

• 褪黑激素的免疫调节作用在患有唐氏综合症的儿童中得到了显着影响，全血样本中 MyD88、IL-1ß 和 NLRP3 的表达减少。

• 褪黑激素是一种拟议中的抗炎药，具有公认的安全性，有可能在小儿唐氏综合症队列中减轻促炎和抗炎细胞因子，但还需要进一步的临床试验。