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

Significance

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the metabolism of tryptophan and plays critical roles in immune regulation to avoid severe immunopathology. We demonstrate that IFN-γ signaling in lung parenchyma prevents idiopathic pneumonia syndrome by inducing IDO expression; inhibition of deacetylation of STAT3 potentiates IDO expression induced by IL-6 in an IFN-γ–independent manner; inhibition of IDO expression by immunosuppressants can be reversed by a histone deacetylase inhibitor; and finally, l-kynurenine acts on lung epithelial cells and CD4 ⁺ T cells through the aryl hydrocarbon receptor to suppress their inflammatory activities. Our results indicate that proinflammatory IFN-γ and IL-6 expressed within a short time range early after pulmonary inflammation is indispensable in protecting the lung from devastating immunopathology.

Abstract

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.