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울산대학교 생명과학부

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Blood, June 2 2022; 139(2):3325-3339 | https://doi.org/10.1182/blood.2021013849 Aryl hydrocarbon receptor-targeted therapy of CD4+ T-cell-mediated idiopathic pneumonia syndrome in mice

Soung-Min Lee ¹, Chae Eun Kim ², Ha Young Park ², Eun Hye Yoon ³, Hae Jeong Won ³, Joo Mi Ahn ⁴, Nu Zen Na Nguyen ⁵, Minji Kim ⁵, Won Hee Jang ¹, Won Sik Lee ⁶, Mi Seon Kang ⁶, Myeonggyo Jeong ⁷, Hwayoung Yun ⁷, Suhyun Park ⁸, Sangwook Wu ⁸, Dong Hyun Kim ¹, Byungsuk Kwon ^5,*, Su-Kil Seo ^1,*

¹Parenchyma Biotech, Korea, Republic of.
²College of Medicine Inje University, Busan, Korea, Republic of.
³Parenchyma Biotech, Busan, Korea, Republic of.
⁴College of Medicine Inje University, Busan, Korea-Demo PeopleS Rep.
⁵University of Ulsan, Ulsan, Korea, Republic of.
⁶College of Medicine Inje University, Korea, Republic of.
⁷Pusan National University, Busan, Korea, Republic of.
⁸Pukyong National University, Busan, Korea, Republic of.

^*Corresponding author.

Abstract

We previously demonstrated that IFN-γ derived from donor T cells co-opts the indoleamine 2,3-dioxygenase 1 (IDO1) à aryl hydrocarbon receptor (AHR) axis to suppress idiopathic pneumonia syndrome (IPS). Here we report that the dysregulated expression of AP-1 family genes in Ahr^-/- lung epithelial cells exacerbated IPS in allogeneic bone marrow transplantation settings. AHR repressed transcription of Jund by preventing STAT1 from binding to its promoter. As a consequence, decreased IL-6 impaired the differentiation of CD4⁺ T cells toward Th17 cells. IFN-γ- and IDO1-independent induction of Ahr expression indicated that the AHR agonist might be a better therapeutic target for IPS than the IDO1 activator. We developed a novel synthetic AHR agonist (referred to here as PB502) that potently inhibits Jund expression. PB502 was highly effective at inducing AHR activation and ameliorating IPS. Notably, PB502 was by far superior to the endogenous AHR ligand, L-Kynurenine, in promoting the differentiation of both mouse and human FoxP3⁺ regulatory CD4⁺ T cells. Our results suggest that the IDO1-AHR axis in lung epithelial cells is associated with IPS repression. A specific AHR agonist may exhibit therapeutic activity against inflammatory and autoimmune diseases by promoting Treg cell differentiation.

논문정보

형식Research article
게재일2022년 06월 (BRIC 등록일 2022-06-03)
연구진국내 연구진
분야 의약학 > 면역의학

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