El Ali Zeina, Deloménie Claudine, Botton Jérémie, Pallardy Marc, Kerdine-Römer Saadia
UMR996 - Inflammation, Chemokines and Immunopathology-, INSERM, Univ Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.
IFR141 IPSIT, Univ Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
Toxicol Appl Pharmacol. 2017 May 1;322:41-50. doi: 10.1016/j.taap.2017.02.014. Epub 2017 Feb 20.
Dendritic cells (DC) are known to play a major role during contact allergy induced by contact sensitizers (CS). Our previous studies showed that Nrf2 was induced in DC and controlled allergic skin inflammation in mice in response to chemicals. In this work, we raised the question of the role of Nrf2 in response to a stress provoked by chemical sensitizers in DC. We used two well-described chemical sensitizers, dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA), known to have different chemical reactivity and mechanism of action. First, we performed a RT-qPCR array showing that CinA was a higher inducer of immune and detoxification genes compared to DNCB. Interestingly, in the absence of Nrf2, gene expression was dramatically affected in response to DNCB but was slightly affected in response to CinA. These observations prompted us to study DC's cell death in response to both chemicals. DNCB and CinA increased apoptotic cells and decreased living cells in the absence of Nrf2. The characterization of DC apoptosis induced by both CS involved the mitochondrial-dependent caspase pathway and was regulated via Nrf2 in response to both chemicals. Oxidative stress induced by DNCB, and leading to cell death, was regulated by Nrf2. Unlike CinA, DNCB treatment provoked a significant reduction of intracellular GSH levels and up-regulated bcl-2 gene expression, under the control of Nrf2. This work underlies that chemical reactivity may control Nrf2-dependent gene expression leading to different cytoprotective mechanisms in DC.
已知树突状细胞（DC）在接触性致敏剂（CS）诱导的接触性过敏反应中起主要作用。我们之前的研究表明，Nrf2在DC中被诱导，并在小鼠体内控制对化学物质产生的过敏性皮肤炎症。在这项研究中，我们提出了Nrf2在应对DC中化学致敏剂引发的应激反应时所起作用的问题。我们使用了两种广为人知的化学致敏剂，二硝基氯苯（DNCB）和肉桂醛（CinA），它们具有不同的化学反应性和作用机制。首先，我们进行了逆转录定量聚合酶链反应（RT-qPCR）阵列分析，结果表明与DNCB相比，CinA是免疫和解毒基因的更强诱导剂。有趣的是，在缺乏Nrf2的情况下，基因表达对DNCB的反应受到显著影响，但对CinA的反应影响较小。这些观察结果促使我们研究DC对这两种化学物质的细胞死亡反应。在缺乏Nrf2的情况下，DNCB和CinA均增加了凋亡细胞数量并减少了活细胞数量。两种CS诱导的DC凋亡的特征涉及线粒体依赖性半胱天冬酶途径，并在对两种化学物质的反应中受Nrf2调节。DNCB诱导的导致细胞死亡的氧化应激受Nrf2调节。与CinA不同，在Nrf2的控制下，DNCB处理导致细胞内谷胱甘肽（GSH）水平显著降低，并上调了bcl-2基因表达。这项研究表明，化学反应性可能控制Nrf2依赖性基因表达，从而在DC中导致不同的细胞保护机制。
