Repression of the aryl-hydrocarbon receptor prevents oxidative stress and ferroptosis of intestinal intraepithelial lymphocytes.

ABSTRACT: The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr^-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr^-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr^-/- IELs. Loss of IELs in Ahrr^-/- m

SUBMITTER: Panda SK 

PROVIDER: S-EPMC10101911 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature