Nrf2-driven CD36 and HO-1 gene expression in circulating monocytes correlates with favourable clinical outcome in pregnancy-associated malaria.
Nrf2-driven CD36 and HO-1 gene expression in circulating monocytes correlates with favourable clinical outcome in pregnancy-associated malaria.
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DOI：
10.1186/s12936-015-0888-8
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发表时间：
2015-09-18
期刊：
影响因子：
3
通讯作者：
Coste A
中科院分区：
文献类型：
--
作者：
Aubouy A;Olagnier D;Bertin G;Ezinmegnon S;Majorel C;Mimar S;Massougbodji A;Deloron P;Pipy B;Coste A
妊娠相关疟疾（PAM）是最严重的疟疾感染形式之一，导致胎儿生长受限和婴儿死亡的高风险。病理学的严重性很大程度上归因于胎盘中单核细胞和巨噬细胞的募集，胎盘血液中发现的炎症失调证明了这一点。重要的是，CD36+单核细胞/巨噬细胞还被认为通过消除凋亡细胞和感染疟疾的红细胞、氧化形式的低密度脂蛋白的内化和再循环以及在促炎反应中与TLR2协作，参与疟原虫检测后促炎和抗炎反应的严格控制。有趣的是，之前的研究表明，在刺激 Nrf2 转录因子后，炎症巨噬细胞上的 CD36 表达上调，而 PPARγ 通路在相同的炎症条件下受到抑制且不起作用。目前的这项研究探讨了 Nrf2 驱动的基因表达、CD36 和血红素加氧酶-1 (HO-1) 在 PAM 临床结果中的可能作用。从 27 名患有 PAM 的女性中收集了临床数据和生物样本，包括外周血单核细胞。多色流式细胞术用于表征先天免疫细胞亚群并量化单核细胞上的 CD36 蛋白表达水平。 CD36、PPARγ、Nrf2 和 HO-1 的 mRNA 水平通过 qPCR 测定，并与临床结果相关。最后，还研究了单核细胞在罗格列酮或萝卜硫素（两种各自的 PPARγ 或 Nrf2 激活剂）处理后调节 CD36 表达的能力。 CD36 受体主要由 CD14+ 循环单核细胞表达，在统计学上与婴儿出生体重的增加相关。有趣的是，转录因子 Nrf2 和酶 HO-1 的 mRNA 水平也与较低的寄生虫血症和增加的婴儿出生体重相关，而 PPARγ mRNA 水平则不然。最后，从低婴儿出生体重孕妇中分离出的单核细胞能够通过 Nrf2 途径离体上调 CD36。总而言之，这些结果表明，先天免疫细胞上 Nrf2 驱动的 CD36 和 HO-1 表达可能有助于 PAM 期间的保护和解毒机制。然而，需要更多的动力和机制研究来加强这项研究的结论。本文的在线版本 (doi:10.1186/s12936-015-0888-8) 包含补充材料，可供授权用户使用。
Pregnancy-associated malaria (PAM) constitutes one of the most severe forms of malaria infection leading to fetal growth restriction and high risk of infant death. The severity of the pathology is largely attributed to the recruitment of monocytes and macrophages in the placenta which is evidenced by dysregulated inflammation found in placental blood. Importantly, CD36+ monocytes/macrophages are also thought to participate in the tight control of the pro- and anti-inflammatory responses following Plasmodium detection through elimination of apoptotic cells and malaria-infected erythrocytes, internalization and recycling of oxidized forms of low-density lipoprotein and collaboration with TLR2 in pro-inflammatory response. Interestingly, previous work demonstrated that CD36 expression was upregulated on inflammatory macrophages following stimulation of the Nrf2 transcription factor, whilst the PPARγ pathway was inhibited and non-functional in the same inflammatory conditions. This current study examined the possible role of Nrf2-driven gene expression, CD36 and Haem-Oxygenase-1 (HO-1), in PAM clinical outcomes. Clinical data and biological samples including peripheral blood mononuclear cells were collected from 27 women presenting PAM. Polychromatic flow cytometry was used to characterize innate immune cell subpopulations and quantify CD36 protein expression level on monocytes. mRNA levels of CD36, PPARγ, Nrf2 and HO-1 were determined by qPCR and related to clinical outcomes. Finally, the capacity of monocytes to modulate CD36 expression upon rosiglitazone or sulforaphane treatment, two respective PPARγ or Nrf2 activators, was also investigated. The CD36 receptor, mostly expressed by CD14+ circulating monocytes, statistically correlated with increased infant birth weights. Interestingly, mRNA levels of the transcription factor Nrf2 and the enzyme HO-1 also correlated with lower parasitaemia and increased infant birth weight, while PPARγ mRNA levels did not. Finally, monocytes isolated from low infant birth weight pregnant women were capable of up-regulating CD36 via the Nrf2 pathway ex vivo. Altogether these results suggest that Nrf2-driven CD36 and HO-1 expression on innate immune cells could contribute to a protective and detoxifying mechanism during PAM. More powered and mechanistical studies are however needed to strengthen the conclusions of this study. The online version of this article (doi:10.1186/s12936-015-0888-8) contains supplementary material, which is available to authorized users.