Interferon Lambda Upregulates IDO1 Expression in Respiratory Epithelial Cells After Influenza Virus Infection

Abstract

Influenza infection causes an increase in indoleamine 2, 3-dioxygenase (IDO) activity in the lung parenchyma. IDO catabolizes tryptophan into kynurenine, leading to immune dampening. Multiple cell types express IDO, and while IFN-γ upregulates IDO in dendritic cells and macrophages, it is unclear how IDO is affected in respiratory epithelial cells during influenza infection. In this study, the role of IFN-λ in IDO regulation was investigated after influenza infection of respiratory epithelial cells. IDO1 expression increased concurrently with IFN-λ expression. In differentiated NHBE cells, the IDO metabolite was released basolaterally. Recombinant IFN-λ upregulated IDO1 activity, and silencing of IFN-λ decreased IDO1 expression during influenza infection. During IFN-λ stimulation, most differentiated cell types are able to express IDO but during influenza infection, IDO is primarily expressed in uninfected cells. These studies show a role for IDO in the host response to influenza infection, and they provide insights into novel approaches for enhancing vaccine responses and therapeutic approaches.

Role of indoleamine 2,3-dioxygenase in health and disease

“…In contrast, recent in vitro data from a murine alveolar epithelial cell line (MLE-15 cells) and primary human bronchial epithelial cells show that influenza induces IDO1 in these cells via IFNλ (type III IFN) and that IDO1 induced in this manner acts to promote infection [81]; whether this is a reflection of the in vivo situation, however, is unknown.…”

“…The binding of TNFα to its receptor stimulates the NF-κB (nuclear factor κB) pathway, enhancing IRF1 transcription and STAT1 activation to up-regulate the expression of IFNγ receptors, thereby potentiating IFNγ signalling [66,[74][75][76][77]. Other stimuli that can induce IDO1 expression in various cell types, either singly or in combination with IFNγ , include type I IFNs (IFNα and IFNβ), IFNλ, IL (interleukin)-1 and IL-6, TLR (Toll-like receptor) 3, 4, 7, 8 and 9 ligands, thymosin α 1 , oestrogen, PGE 2 (prostaglandin E 2 ), muramyl tripeptide, α-galactosylceramide, glucocorticoids and haemoglobin [74,75,[78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95][96] and certain infectious pathogens (discussed in detail in the 'IDO1 and host response to microbial infection' section below).…”

“…An increasing number of studies report that infection of cells in vitro with virus alone induces IDO1 expression and activity. For example, IDO1 induction has been reported in human monocyte-derived macrophages infected with HIV [522], the flaviviruses West Nile virus and Japanese encephalitis virus [108,523] and Epstein-Barr virus [94], in human pigment retinal epithelial cells infected with West Nile virus [523], and influenza virus-infected primary human airway epithelial cells [81,524] and a mouse lung epithelial cell line [81].…”

“…With respect to this, Liu et al [94] recently reported that the ability of Epstein-Barr virus to induce IDO1 in human monocyte-derived macrophages required TNFα and IL-6 synthesis, both of which up-regulated IDO1 expression via NF-κB and p38 MAPK signalling pathways. IFNλ, expressed by human and mouse lung epithelial cells following influenza infection, also elicits IDO1 expression and activity [81].…”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

“…Interestingly, 41 of the 199 druggable cellular factors were shown to be implicated in IAV infection (Table S2) [10,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,...…”