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

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.

Immune regulation through tryptophan metabolism

“…AHR activation signature genes include those relevant to inflammation and anti-inflammatory processes, suggesting that AHR induces the expression of immunoregulatory genes directly or indirectly in DCs 18 . In contrast, AHR is likely to repress the expression of inflammatory genes by inhibiting transcription factors that are critical in inflammation (for example, STAT1, AP1, and NF-κB) based on results obtained from macrophages and epithelial cells [19][20][21] . Studies by Gargaro et al suggest that Kyn production by IDO1 + cDC1s is indispensable for self-tolerance, which is consistent with results showing that cDC1s are required for immunological tolerance induced by apoptotic cells 22,23 .…”

“…Some microbes of the microbiota and ingested food also provide AHR ligands, which play a protective role against either intestinal infection or an immune attack directed against the microbiota or other pathogens (discussed later). In allogeneic hematopoietic stem cell transplantation (HSCT) animal models, we demonstrated that IFN-γ from donor CD4 + T cells and inflammatory cytokines of the host, including IL-1β and TNF-α, induce the expression of IDO1 and AHR, respectively, through NF-κB activation in alveolar epithelial cells 21 , 54 . This cell-intrinsic IDO1-AHR pathway represses STAT1-mediated IL6 expression and subsequently prevents CD4 + T cells from differentiating into pathogenic Th17 cells, which are a major effector responsible for idiopathic pneumonia syndrome (IPS) (Fig.…”

“…Recently, AHR agonists with drug-like properties have been reported 109 . We also developed a novel synthetic indole-3-acetamide analog (PB502), a potent AHR agonist with therapeutic activity against IPS and gut GVHD 21 . PB502 effectively suppressed Th17 cells while promoting the generation of Tregs in the lungs of HSCT recipients.…”