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.
Competing Interest Statement
The authors have declared no competing interest.