Aryl hydrocarbon receptor–targeted therapy for CD4+ T cell–mediated idiopathic pneumonia syndrome in mice

Author:

Lee Soung-Min12ORCID,Kim Chae Eun1,Park Ha Young1,Yoon Eun Hye2ORCID,Won Hae Jeong2,Ahn Joo Mi1,Nguyen Nu Zen Na3ORCID,Kim Minji3,Jang Won Hee24,Lee Won-Sik5,Kang Mi Seon6ORCID,Jeong Myeonggyo7,Yun Hwayoung7ORCID,Park Suhyun8,Wu Sangwook8,Kim Dong Hyun29ORCID,Kwon Byungsuk3ORCID,Seo Su-Kil12ORCID

Affiliation:

1. 1Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, Republic of Korea;

2. 2Parenchyma Biotech, Busan, Republic of Korea;

3. 3BK21 Integrated Immunomodulation Education and Research Team, School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea;

4. 4Department of Biochemistry, College of Medicine, Inje University, Busan, Republic of Korea;

5. 5Division of Hemato-Oncology, Department of Internal Medicine, and

6. 6Department of Pathology, Busan Paik Hospital, College of Medicine, Inje University, Busan, Republic of Korea;

7. 7Department of Manufacturing Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea;

8. 8Department of Physics, Pukyong National University, Busan, Republic of Korea; and

9. 9Department of Pharmacology, College of Medicine, Inje University, Busan, Republic of Korea

Abstract

Abstract We previously demonstrated that interferon γ (IFN-γ) derived from donor T cells co-opts the indoleamine 2,3-dioxygenase 1 (IDO1) → 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 interleukin-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 regulatory T-cell differentiation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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