Silencing of aryl hydrocarbon receptor repressor restrains Th17 cell immunity in autoimmune hepatitis

Gao et al., Journal of Autoimmunity, 2024, asked why Th17 cells from people with autoimmune hepatitis fail to respond to the aryl hydrocarbon receptor. The suspect was the receptor's own repressor, AHRR. Working with Th17 cells from 30 patients and 30 healthy controls, the group found that AHRR is markedly raised in patient cells exposed to L-kynurenine, and that removing AHRR restores the response, raising CYP1A1 and lowering IL17A. Those cell-culture experiments used a commercial small interfering RNA and not AUM material.

The in vivo arm is the AUM work. NOD/scid/gamma mice were reconstituted with human CD4 T cells from a healthy donor, checked 3 weeks later for more than 10% human chimerism, then given a single intraperitoneal dose at 5.4 mg/kg of an AUMsilence sdASO raised against the human AHRR transcript, or the matched scramble control. Seventy-two hours later the animals received concanavalin A at 20 mg/kg intravenously and were taken 4 hours after that. Eight mice received the scramble and seven received the AHRR oligonucleotide.

Silencing AHRR lowered serum alanine aminotransferase and reduced the inflammatory infiltrate in the liver on histology. Inside the liver the human CD4 cells shifted toward a regulatory profile: FOXP3 positive and IL10 positive fractions rose and the IL17A positive fraction fell, while CD39 positive, interferon gamma positive and double positive fractions did not move. The spleen of the same animals was unchanged in histology, in human CD3 infiltrate and in every CD4 subset measured, so the effect tracked the organ under attack. Two points of care for anyone citing this paper: the oligonucleotide was raised against the human sequence and read out in human cells carried by the mouse, and the company name is misspelled in the Methods.