Uremic toxin indoxyl sulfate induces trained immunityviathe AhR-dependent arachidonic acid pathway in end-stage renal disease (ESRD)

Abstract

Trained immunity is the long-term functional reprogramming of innate immune cells following exposure to various insults that results in altered responses towards a secondary challenge. Indoxyl sulfate (IS) is a potent uremic stimulus associated with inflammation in chronic kidney disease (CKD). However, the impact of IS on trained immunity remains unknown. Here, we find that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production upon LPS-stimulation. Further, the aryl hydrocarbon receptor contributes to IS-trained immunity by enhancing expression of arachidonic acid metabolism-related genes ALOX5 and ALOX5AP. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and healthy monocytes trained with uremic sera from ESRD patients exhibit increased TNF-α and IL-6 production. Moreover, IS-trained mice have augmented TNF-α production following LPS-stimulation. These results provide insight into the role of IS in trained immunity, which is critical during inflammatory responses in CKD patients.

The AKI-to-CKD Transition: The Role of Uremic Toxins

“…In vitro -↑ AhR-dependent arachidonic acid pathway-reprogramming monocytes [126] In vivo -Alteration of metabolic pathways, including tryptophan metabolism [127] Epigenetic In vivo…”

“…Hopp et al showed a link between kidney damage, metabolic reprogramming, and the accumulation of UTs, where an alteration in tryptophan metabolism was associated with a deterioration in kidney function and the accumulation of UTs in an in vivo model of autosomal dominant polycystic kidney disease [127]. UTs also stimulate inflammation via an AhR-dependent reprogramming of arachidonic acid metabolism [126].…”