PDF(Pubmed)
Abstract：
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
摘要：
训练免疫是先天性免疫细胞的长期功能重编程，这导致对次要挑战的反应改变。尽管硫酸吲哚酚（IS）是与慢性肾病（CKD）相关的炎症相关的有效刺激，它对受过训练的免疫力的影响尚未被研究。这里,我们证明IS通过表观遗传和代谢重编程诱导单核细胞中训练的免疫，导致细胞因子产生增加。机械上,芳香烃受体(AhR)通过增强花生四烯酸(AA)代谢相关基因如花生四烯酸5-脂氧合酶(ALOX5)和ALOX5激活蛋白(ALOX5AP)的表达来促进IS训练的免疫。在IS训练期间抑制AhR抑制了IS训练的免疫的诱导。终末期肾病（ESRD）患者的单核细胞ALOX5表达增加，训练6天后，它们对脂多糖(LPS)表现出增强的TNF-α和IL-6产生。此外，用ESRD患者的尿毒症血清训练的健康对照来源的单核细胞显示TNF-α和IL-6的产生增加。始终如一，与对照小鼠相比，IS训练的小鼠及其脾骨髓细胞在体内和离体LPS刺激后的TNF-α产生增加。这些结果提供了深入了解IS在诱导训练免疫中的作用，这在CKD患者的炎症免疫反应中至关重要。
