Journal Article

Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

Yun, Hwayoung, Kim, Juyang, Park, Sae-Gwang, Choi, Inhak, Choi, Il-Whan, Lee, Soung-Min, Teshima, Takanori, Yoon, Eun Hye, Suh, Young-Sill, Kang, Sun-Woo, Kwon, Byungsuk, Park, Ha Young, Jang, Won Hee, Lee, Won-Sik, Seo, Su-Kil

2017

Overview

The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4⁺ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ–dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ–independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, L-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4⁺ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

• Publisher: National Academy of Sciences
• Subject: Alveoli / Animals / Antigens / Aromatic compounds / Basic Helix-Loop-Helix Transcription Factors - immunology / Basic Helix-Loop-Helix Transcription Factors - metabolism / Biological Sciences / CD4 antigen / Clonal deletion / Deacetylation / Epithelial cells / Female / Gene deletion / Gene expression / Graft vs Host Disease / Hematopoietic Stem Cell Transplantation - mortality / Histone deacetylase / Histone Deacetylase Inhibitors - pharmacology / Hydrocarbons / Idiopathic pneumonia syndrome / Immune response / Immune system / Immunology / Immunology and Inflammation / Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics / Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism / Inflammation / Interferon / Interferon gamma Receptor / Interferon-gamma - genetics / Interferon-gamma - metabolism / Interferon-gamma - pharmacology / Interleukin 6 / Kynurenine - metabolism / Lung - immunology / Lung - metabolism / Lung - pathology / Lungs / Lymphocytes / Lymphocytes T / Macrophages / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Mutant Strains / Parenchyma / PNAS Plus / Pneumonia - drug therapy / Pneumonia - metabolism / Receptors, Aryl Hydrocarbon - immunology / Receptors, Aryl Hydrocarbon - metabolism / Receptors, Interferon - genetics / Receptors, Interferon - metabolism / Stat3 protein / Stem cell transplantation / Stem cells / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / T-Lymphocytes, Regulatory - immunology / Tacrolimus / Tacrolimus - pharmacology / Transplantation / Tryptophan 2,3-dioxygenase