Itaconate regulates macrophage function through stressful iron-sulfur cluster disrupting and iron metabolism rebalancing
Itaconate regulates macrophage function through stressful iron-sulfur cluster disrupting and iron metabolism rebalancing
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衣康酸通过应激性铁硫簇破坏和铁代谢重新平衡调节巨噬细胞功能
DOI：
10.1096/fj.202100726rr
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发表时间：
2021-10-01
期刊：
影响因子：
4.8
通讯作者：
Li, Guangping
中科院分区：
文献类型：
--
作者：
Liu, Xing;Shi, Bingshuo;Li, Guangping
脂多糖(LPS)刺激的巨噬细胞表达一种乌头酸脱羧酶(IRG1，又称ACOD1)，导致内源性代谢物衣康酸的积累。然而，衣康酸水平升高改变巨噬细胞功能的确切机制尚不清楚。我们的假设是衣康酸通过某种不确定的机制影响巨噬细胞的功能。在此基础上，我们建立了衣康酸刺激巨噬细胞的转录和蛋白质组学特征，并确定了IL-1β分泌和铁代谢改变的途径。在IRG1基因敲除的THP-1细胞系中，IRG1缺陷对IL-1β分泌和铁代谢的影响一直得到证实。几种常见的抑制剂和其他化合物被用来研究所涉及的分子机制。只有半胱氨酸和抗氧化剂(水合儿茶素)可以抑制。衣康酸刺激的巨噬细胞caspase-1激活和IL-1β分泌。我们进一步发现，衣康酸刺激降低了乌头酸酶的活性。我们的结果表明，线粒体乌头酸酶(ACO2，一种三羧酸循环酶)或胞浆乌头酸酶(ACO1，一种铁调节蛋白)的过度表达对IL-1β的分泌和铁代谢的改变具有拮抗作用。这两种酶的活性都被衣康酸抑制，这是因为铁-硫(Fe-S)簇的破坏。我们的研究结果表明，irg1和衣康酸对巨噬细胞的免疫调节作用是应激性铁-S乌头酸酶簇的破坏和铁代谢的再平衡。
Lipopolysaccharide (LPS)-stimulated macrophages express an aconitate decarboxylase (IRG1, also called ACOD1), leading to accumulation of the endogenous metabolite itaconate. However, the precise mechanisms by which elevated itaconate levels alter macrophage function are not clear. Our hypothesis is itaconate affects macrophage function through some uncertain mechanism. Based on this, we established a transcriptional and proteomic signature of macrophages stimulated by itaconate and identified the pathways of IL-1 beta secretion and altered iron metabolism. Consistently, the effect of IRG1 deficiency on IL-1 beta secretion and iron metabolism was confirmed in IRG1 knockout THP-1 cell lines. Several common inhibitors and other compounds were used to examine the molecular mechanisms involved. Only cysteine and antioxidants (catechin hydrate) could inhibit. caspase-1 activation and IL-1 beta secretion in itaconate-stimulated macrophages. We further found that aconitase activity was decreased by itaconate stimulation. Our results demonstrate the counteracting effects of overexpression of mitochondria] aconitase (ACO2, a tricarboxylic acid cycle enzyme) or cytosolic aconitase (ACO1, an iron regulatory protein) on IL-1 beta secretion and altered iron metabolism. Both enzyme activities were inhibited by itaconate because of iron-sulfur (Fe-S) cluster destruction. Our findings indicate that the immunoregulatory functions of IRG1 and itaconate in macrophages are stressful Fe-S cluster of aconitases disrupting and iron metabolism rebalancing.