Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany.
Institute of Biochemistry, Leipzig University, Leipzig, Germany.
Front Immunol. 2021 Mar 31;12:620270. doi: 10.3389/fimmu.2021.620270. eCollection 2021.
Emerging studies revealed that the Aryl hydrocarbon receptor (AhR), a receptor sensing environmental contaminants, is executing an immunomodulatory function. However, it is an open question to which extent this is achieved by its role as a transcription factor or non-genomic signaling. We utilized a multi-post-translational modification-omics approach to examine non-genomic AhR-signaling after activation with endogenous (FICZ) or exogenous (BaP) ligand in endotoxin-activated (LPS) monocyte-derived macrophages. While AhR activation affected abundances of few proteins, regulation of ubiquitination and phosphorylation were highly pronounced. Although the number and strength of effects depended on the applied AhR-ligand, both ligands increased ubiquitination of Rac1, which participates in PI3K/AKT-pathway-dependent macrophage activation, resulting in a pro-inflammatory phenotype. In contrast, co-treatment with ligand and LPS revealed a decreased AKT activity mediating an anti-inflammatory effect. Thus, our data show an immunomodulatory effect of AhR activation through a Rac1ubiquitination-dependent mechanism that attenuated AKT-signaling, resulting in a mitigated inflammatory response.
新兴研究表明，芳烃受体（AhR）作为一种感知环境污染物的受体，具有免疫调节功能。然而，其作为转录因子或非基因组信号转导发挥作用的程度仍不清楚。我们利用多种翻译后修饰组学方法，在内毒素激活（LPS）的单核细胞衍生巨噬细胞中，检测内源性（FICZ）或外源性（BaP）配体激活 AhR 后非基因组信号转导。虽然 AhR 激活会影响少数蛋白质的丰度，但泛素化和磷酸化的调节作用非常显著。尽管所应用的 AhR 配体的数量和强度不同，但两种配体均增加了 Rac1 的泛素化，Rac1 参与 PI3K/AKT 通路依赖性巨噬细胞激活，导致促炎表型。相比之下，配体和 LPS 的共同处理会降低 AKT 活性，从而发挥抗炎作用。因此，我们的数据表明 AhR 激活通过 Rac1 泛素化依赖的机制发挥免疫调节作用，该机制减弱了 AKT 信号转导，从而减轻了炎症反应。
