Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis

Abstract

Liver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11c+DCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11c+CD80+, CD11c+CD86+, CD11c+MHCII+, and CD11c+CD40+ cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11c+DCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1−/− mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.

Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma

“…ERO1a has been shown to regulate MDSC induction via GM-CSF and CXCL1/2 secretion (15), whereas IDO1 promotes MDSCs and M2 anti-inflammatory macrophages expansion through tryptophan catabolism (19). Particularly, a recent study presented the overexpression of IDO1 inhibited DC maturation and consequently affected immune cell recruitment in an inflammatory liver model (47). Our study identified a 12-fold reduction in hypoxia signaling, emphasizing the potential of combining ERO1a and IDO1 as hypoxia-driven immune checkpoints.…”

Endogenous Follistatin-like 1 guarantees the immunomodulatory properties of mesenchymal stem cells during liver fibrotic therapy

“…IDO, the rate-limiting enzyme in the kynurenine pathway of tryptophan degradation, plays an important role in inflammation. It has been reported that IDO can not only affect the infiltration of immune cells in many pathological disease conditions, including liver fibrosis [ 30 , 31 ], but also further inhibits T cell proliferation and promotes anti-inflammatory macrophage differentiation during MSC therapy [ 29 , 32 ]. Based on the results of our RNA-seq analysis, we hypothesized that IDO was one of the target genes of FSTL1.…”

Immune microenvironment changes of liver cirrhosis: emerging role of mesenchymal stromal cells

“…Interaction between immune cells resulted in the increased expression of CCL20 in NAFLD fibrosis patients ( 106 ). Indoleamine 2,3-dioxygenase 1 (IDO1), an immunomodulatory enzyme, was highly expressed in choledochotomy (BDL)-induced mice, inhibiting DCs maturation and T cell proliferation from recruiting immune cells and promoting hepatic fibrosis ( 107 ).…”