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

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.acute lethal pulmonary inflammation | IFN-γ | Th2/Th17 cells | indoleamine 2,3-dioxygenase | aryl hydrocarbon receptor I ndoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme of tryptophan catabolism along the kynurenine pathway. The immunosuppressive mechanism of IDO is mediated by depletion of tryptophan and/or the accumulation of catabolites collectively known as kynurenines (1-5). Recently, L-kynurenine, a product of IDO, has been identified as an endogenous ligand for the aryl hydrocarbon receptor (AhR), which is a ligand-activated transcription factor belonging to the steroid receptor family (6, 7). It is now clear that the IDO-AhR pathway contributes to immune homeostasis by promoting modulation of innate and adaptive immune responses. Whereas IFN-γ is the most prominent inducer of IDO in various cell types, IL-6 also can induce the enzyme expression in astrocytes and neuronal and cancer cells by stimulating the JAK/ STAT3 signaling pathway (8, 9). By contrast, IL-6 has been implicated in the pathophysiology of Th17-mediated pulmonary inflammations such as idiopathic pulmonary syndrome (IPS) (10, 11). Thus, the IL-6-STAT3 pathway might be immunosuppressive or immunostimulatory in a context-dependent way.The lung was evolved to develop tolerance mechanisms to avoid severe immunopathology during the immune response to pathogens (12, 13). High levels of IDO are expressed in the lung during microbial infections. IFNs seem to be required for IDO expression by microbial components (14, 15) and IDO expressed in epithelial cells prevents immunopathology mediated by Th cells after microbial infections (16). It is clear that defects in IDO expression in cystic fibrosis and granulomatous disease is associated with unchecked inflammation cause...

Ozone-Induced Aryl Hydrocarbon Receptor Activation Controls Lung Inflammation via Interleukin-22 Modulation

“…AhR plays a key role of tryptophan metabolism. Since the 1980s, several studies reported a role of tryptophan metabolites in the lung, including in cancer (59) and chronic inflammatory lung diseases affecting the parenchyma, such as sarcoidosis and idiopathic fibrosis (1,60). The indole/tryptamine pathway could induce the production of several indole from tryptophan that may activate AhR.…”

Indoleamine 2,3-Dioxygenase Regulates Macrophage Recruitment, Polarization and Phagocytosis in Aspergillus Fumigatus Keratitis

“…11,20 It has been reported that IDO may perform a pathogenic role in the progression of the inflammatory diseases. [21][22][23] IDO can change the function of Downloaded from iovs.arvojournals.org on 11/02/2020 FIGURE 5. Effects of IDO on the polarization of mouse peritoneal primary macrophages.…”

Metabolic reprograming of LPS-stimulated human lung macrophages involves tryptophan metabolism and the aspartate-arginosuccinate shunt

“…Hence, the depletion of tryptophan is the consequence of both the LPS-induced increase in indoleamine-2,3-dioxygenase (IDO), leading to the formation of kynurenine metabolites, as described in human pulmonary macrophages [56] and to the increase in tryptophan hydroxylase (TPH) activity, also occurring in macrophages in inflammatory conditions [57]. The effectors of the kynurenine pathway, expressed in epithelial cells and alveolar macrophages, were previously shown to be critical regulators of acute pulmonary inflammation in a murine model of lung transplantation [58]. In infectious disease models, IDO expression is increased by respiratory syncytial virus in human monocyte-derived dendritic cells and by IFN-γ and HIV in human monocyte-derived macrophages [59,60] and quinolinate is increased by HIV in monocyte-derived macrophages [49].…”