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Human IFN-λ3 and IFN-λ4 show distinct molecular phenotypes in macrophages

ABSTRACT: CD14+ cells were used to obtain M1 or M2-MDMs in presence of recombinant human IFN-λ3 or IFN-λ4. Briefly, four Caucasian donors (n=4; one female and three males) in between 31-41 y of age, were used to obtain highly homogenous CD14+ cells; these were purchased from a commercial source. The CD14+ cells were incubated with GM-CSF (for M1-MDM) or M-CSF (for M2-MDM) in presence or absence of IFN-λ3 (at 50 ng/ml) or IFN-λ4 (at 6 μg/ml) for six days, and then the cells were fully washed off any residual growth factors or IFNs. After six days of differentiation, the macrophages were matured with LPS for 24 h, then the total cellular RNA was isolated and RNA-seq was performed at QuickBiology, Psadena, CA, USA Summary of the study: Type III interferons or IFN-λs have emerging roles beyond antiviral defense at barrier surfaces. IFN-λ3 and IFN-λ4 are genetically associated with several infectious and inflammatory diseases; however, strong linkage at the IFNL locus circumvents a clearer understanding of their differential influence on the disease phenotypes. Comparative studies to examine the effect of IFN-λ3 and IFN-λ4 on immune cells are lacking. In this study, we used human CD14+ monocytes differentiated into macrophages (MDMs) in presence of IFN-λ3 or IFN-λ4 under M1 or M2 conditions, and after maturation with lipopolysaccharides, to perform RNA-seq analysis in order to understand the changes in molecular phenotypes that may have been induced by the two IFN-λs. Firstly, we found that IFN-λ4 can induce several genes, both unique and common to those induced by IFN-λ3, especially in M1-MDMs; our analysis showed that close to 870 genes (in both cell types) were reciprocally regulated by IFN-λ3 and IFN-λ4. Secondly, the induction of differentially expressed gene pattern suggested that IFN-λ3 has a stronger effect on M2-MDMs compared to M1-MDMs while the reverse is true for IFN-λ4.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182823 | GEO | 2022/03/06

REPOSITORIES: GEO

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Project description:Hepatitis B virus (HBV) causes both acute and chronic liver inflammation. Approximately 600,000 CHB patients each year die of HBV-related diseases such as cirrhosis and liver cancer. Therefore, CHB remains a global health concern. Although there have been anti-HBV agents for treating CHB, they have some limitations including viral-drug resistance and adverse effects. Type III IFN or IFN-λ is promising to use as anti-HBV agents because of its anti-viral activities like type I IFNs. In addition, the expression of its receptor, IFNLR1, is limited only in epithelial cells including hepatocytes. Thus, treatment with IFN-lambda results in less side effects compared to IFN-alpha treatment. IFN-lambdas have been shown to inhibit the replication of several viruses including IAV, DENV, EMCV, HIV, HCV, and HBV; however, there have been no studies on the effects of IFN-λ3, the highest activity among other subtypes, on HBV replication. Therefore, this study aims to determine antiviral activities of IFN-λ3 against HBV replication and to investigate its molecular mechanism responsible for suppressing HBV propagation. The results showed that HBV transcripts and amount of intracellular HBV DNA were decreased in HepG2.2.15 cells, stable HBV-transfected hepatoblastoma cell line, treated with IFN-λ3 in a dose-dependent manner. This indicated that IFN-λ3 could inhibit HBV replication. Next, we performed quantitative proteomics to investigate the proteome changes in HepG2.2.15 treated with IFN-λ3. The proteins that changed their expressions were involved in several biological processes such as defense to viral infection, immune responses, cell-cell adhesion, transcription, translation, and metabolism. We further confirmed the proteomics results by immunoblotting assay. Consistent with MS data, it found that the expression of OAS3, SAMHD1 and STAT1 were increased as a result of IFN-λ3 stimulation. These results indicated that proteomics results were reproducible and reliable. Finally, we proposed 3 possible mechanisms involved in suppressing HBV replication including i.) IFN-λ3 induced anti-viral proteins affecting many steps in HBV life cycle ii.) IFN-λ3 promoted antigen processing and antigen presentation and iii.) IFN-λ3 rescued RIG-I signaling to promote both type I and type III IFN production.

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Human IFN-λ3 and IFN-λ4 show distinct molecular phenotypes in macrophages

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