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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-\u03b1 and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-\u03b1 and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-\u03b1 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.<\/jats:p>","DOI":"10.7554\/elife.87316","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T14:02:19Z","timestamp":1686060139000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.87316","source":"Crossref","is-referenced-by-count":31,"title":["Uremic toxin indoxyl sulfate induces trained immunity via the AhR-dependent arachidonic acid pathway in end-stage renal disease (ESRD)"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3578-7344","authenticated-orcid":true,"given":"Hee Young","family":"Kim","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04h9pn542","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Immunology, Seoul National University College of Medicine","place":["Seoul, Republic of 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