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Monocytes differentiated into macrophages and dendritic cells in the presence of human IFN-λ3 or IFN-λ4 show distinct phenotypes.

ABSTRACT: Human IFN-λ4 is expressed by only a subset of individuals who possess the ΔG variant allele at the dinucleotide polymorphism rs368234815. Recent genetic studies have shown an association between rs368234815 and different infectious and inflammatory disorders. It is not known if IFN-λ4 has immunomodulatory activity. The expression of another type III IFN, IFN-λ3, is also controlled by genetic polymorphisms that are strongly linked to rs368234815. Therefore, it is of interest to compare these two IFNs for their effects on immune cells. Herein, using THP-1 cells, it was confirmed that IFN-λ4 could affect the differentiation status of macrophage-like cells and dendritic cells (DCs). The global gene expression changes induced by IFN-λ4 were also characterized in in vitro generated primary macrophages. Next, human PBMC-derived CD14⁺ monocytes were used to obtain M1 and M2 macrophages and DCs in the presence of IFN-λ3 or IFN-λ4. These DCs were cocultured with CD4⁺ Th cells derived from allogenic donors and their in vitro cytokine responses were measured. The specific activity of recombinant IFN-λ4 was much lower than that of IFN-λ3, as shown by induction of IFN-stimulated genes. M1 macrophages differentiated in the presence of IFN-λ4 showed higher IL-10 secretion than those differentiated in IFN-λ3. Coculture experiments suggested that IFN-λ4 could confer a Th2-biased phenotype to allogenic Th cells, wherein IFN-λ3, under similar circumstances, did not induce a significant bias toward either a Th1 or Th2 phenotype. This study shows for the first time that IFN-λ4 may influence immune responses by immunomodulation.

SUBMITTER: De M

PROVIDER: S-EPMC7611425 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

2022-03-06 | GSE182823 | GEO

Distinct molecular phenotypes involving several human diseases are induced by IFN-λ3 and IFN-λ4 in monocyte-derived macrophages.

Project description:Human Interferon (IFN) lambda 3 (IFN-λ3) and IFN-λ4 are closely linked at the IFNL locus and show association with several diseases in genetic studies. Since they are only ~30% identical to each other, to better understand their roles in disease phenotypes, comparative studies are needed. Monocytes are precursors to macrophages (monocyte-derived macrophages; MDMs) that get differentiated under the influence of various immune factors, including IFNs. In a recent study, we characterized lipopolysaccharide-activated M1 and M2-MDMs that were differentiated in presence of IFN-λ3 or IFN-λ4. In this study, we performed transcriptomics on these M1 and M2-MDMs to further understand their molecular phenotypes. We identified over 760 genes that were reciprocally regulated by IFN-λ3 and IFN-λ4, additionally we identified over 240 genes that are significantly affected by IFN-λ4 but not IFN-λ3. We observed that IFN-λ3 was more active in M2-MDMs while IFN-λ4 showed superior response in M1-MDMs. Providing a structural explanation for these functional differences, molecular modeling showed differences in expected interactions of IFN-λ3 and IFN-λ4 with the extracellular domain of IFN-λR1. Further, pathway analysis showed several human infectious diseases and even cancer-related pathways being significantly affected by IFN-λ3 and/or IFN-λ4 in both M1 and M2-MDMs.

| S-EPMC9042695 | biostudies-literature

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

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

| PRJNA758011 | ENA

IFN-λ4 inhibits HIV infection of macrophages through signalling of IFN-λR1/IL-10R2 receptor complex.

Project description:The recently discovered IFN-λ4 has been found to have antiviral activity against several viruses. However, it's unknown whether IFN-λ4 can inhibit HIV infection. Here, we show that IFN-λ4 could suppress HIV infection of macrophages. This IFN-λ4-mediated HIV inhibition was compromised by the antibodies against IFN-λ receptor complex, IFN-λR1/IL-10R2. IFN-λ4 enhanced the phosphorylation of STAT1, and induced antiviral interferon-stimulated genes. These findings indicated that IFN-λ4 can inhibit HIV via JAK/STAT signalling pathway.

| S-EPMC6286684 | biostudies-literature

Porcine interferon lambda 3 (IFN-λ3) shows potent anti-PRRSV activity in primary porcine alveolar macrophages (PAMs).

Project description:BackgroundPorcine reproductive and respiratory syndrome virus (PRRSV) is a serious viral disease of swine. At present, there are vaccines for the control of PRRSV infection, but the effect is not satisfactory. The recombination of attenuated vaccines causes significant difficulties with the prevention and control of PRRSV. Type III interferons (IFNs), also called IFN-λs, were newly identified and showed potent antiviral activity within the mucosal surface and immune organs.ResultsTherefore, primary porcine alveolar macrophages (PAMs) were used for this investigation. To this end, we found that the replication of PRRSV in PAMs was significantly reduced after pre-treatment with IFN-λ3, and such inhibition was dose- and time-dependent. The plaque formation of PRRSV abrogated entirely, and virus yields were reduced by four orders of magnitude when the primary PAMs were treated with IFN-λ3 at 1000 ng/ml. In addition, IFN-λ3 in our study was able to induce the expression of interferon-stimulated genes 15 (ISG15), 2'-5'-oligoadenylate synthase 1 (OAS1), IFN-inducible transmembrane 3 (IFITM3), and myxoma resistance protein 1(Mx1) in primary PAMs.ConclusionsIFN-λ3 had antiviral activity against PRRSV and can stimulate the expression of pivotal interferon-stimulated genes (ISGs), i.e., ISG15, Mx1, OAS1, and IFITM3. So, IFN-λ3 may serve as a useful antiviral agent.

| S-EPMC7594293 | biostudies-literature

Comparative Functional Analysis of 12 Mammalian IFN-λ4 Orthologs.

Project description:IFN-λ4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individuals--up to 10% of Asians, 50% of Europeans, and 90% of Africans--carry the ΔG allele of a genetic variant rs368234815-TT/ΔG and are genetically able to produce IFN-λ4 protein. Carriers of the ΔG allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-λ4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present the first comparative analysis of 12 mammalian IFN-λ4 orthologs in a human hepatic cell line, HepG2, which supports signaling of the human IFN-λ4. We show that despite differences in protein sequences, functional properties of the recombinant human and nonhuman IFN-λ4 proteins are comparable-they are all expressed as predominantly cytoplasmic proteins that are biologically active for induction of interferon signaling. We show that several IFN-λ4 orthologs can be detected by Western blotting, flow cytometry, and confocal imaging using a monoclonal antibody developed for the human IFN-λ4. Studies of IFN-λ4 in animals should help improve our understanding of the biology of this novel clinically important interferon in normal and disease conditions.

| S-EPMC4722605 | biostudies-literature

Phenotypic and functional profile of IFN-α-differentiated dendritic cells (IFN-DCs) from HIV-infected individuals.

Project description:Dendritic cell (DC)-based immunotherapy is a promising strategy for the treatment of HIV-infected individuals. Different from the conventional protocol for DC differentiation based on the cytokine IL-4 (IL4-DCs), several studies have suggested obtaining DCs by culturing monocytes with type I IFN (IFN-α) to yield IFN-DCs, as performed in cancer therapy. To evaluate the phenotypic and functional characteristics, monocytes from HIV-infected subjects were differentiated into IFN-DCs or IL4-DCs, pulsed with chemically inactivated HIV and stimulated with pro-inflammatory cytokines. A comparative analysis between both types of monocyte-derived DCs (MoDCs) showed that immature IFN-DCs were phenotypically distinct from immature IL4-DCs at the baseline of differentiation, presenting a pre-activated profile. From the functional profile, we determined that IFN-DCs were capable of producing the cytokine IL-12 p70 and of inducing the production of IFN-γ by CD4 + T lymphocytes but not by TCD8+ lymphocytes. Our results suggest that IFN-DCs derived from HIV-infected individuals are able to recognize and present viral antigens to induce TCD4+ cellular immunity to HIV.

| S-EPMC6773379 | biostudies-literature

Zinc is a potent and specific inhibitor of IFN-λ3 signalling.

Project description:Lambda interferons (IFNL, IFN-λ) are pro-inflammatory cytokines important in acute and chronic viral infection. Single-nucleotide polymorphisms rs12979860 and rs8099917 within the IFNL gene locus predict hepatitis C virus (HCV) clearance, as well as inflammation and fibrosis progression in viral and non-viral liver disease. The underlying mechanism, however, is not defined. Here we show that the rs12979860 CC genotype correlates with increased hepatic metallothionein expression through increased systemic zinc levels. Zinc interferes with IFN-λ3 binding to IFNL receptor 1 (IFNLR1), resulting in decreased antiviral activity and increased viral replication (HCV, influenza) in vitro. HCV patients with high zinc levels have low hepatocyte antiviral and inflammatory gene expression and high viral loads, confirming the inhibitory role of zinc in vivo. We provide the first evidence that zinc can act as a potent and specific inhibitor of IFN-λ3 signalling and highlight its potential as a target of therapeutic intervention for IFN-λ3-mediated chronic disease.

| S-EPMC5442324 | biostudies-literature

Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny.

Project description:The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.

| S-EPMC4638219 | biostudies-literature

Diabetic Endothelial Cells Differentiated From Patient iPSCs Show Dysregulated Glycine Homeostasis and Senescence Associated Phenotypes.

Project description:Induced pluripotent stem cells derived cells (iPSCs) not only can be used for personalized cell transfer therapy, but also can be used for modeling diseases for drug screening and discovery in vitro. Although prior studies have characterized the function of rodent iPSCs derived endothelial cells (ECs) in diabetes or metabolic syndrome, feature phenotypes are largely unknown in hiPSC-ECs from patients with diabetes. Here, we used hiPSC lines from patients with type 2 diabetes mellitus (T2DM) and differentiated them into ECs (dia-hiPSC-ECs). We found that dia-hiPSC-ECs had disrupted glycine homeostasis, increased senescence, and impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. These signature phenotypes will be helpful to establish dia-hiPSC-ECs as models of endothelial dysfunction for understanding molecular mechanisms of disease and for identifying and testing new targets for the treatment of endothelial dysfunction in diabetes.

| S-EPMC8201091 | biostudies-literature

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