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

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

PROVIDER: PRJNA758011 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15618960_1.fastq.gz	Fastqsanger.gz
	SRR15618960_2.fastq.gz	Fastqsanger.gz
	SRR15618961_1.fastq.gz	Fastqsanger.gz
	SRR15618961_2.fastq.gz	Fastqsanger.gz
	SRR15618962_1.fastq.gz	Fastqsanger.gz

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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

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

Project description: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.

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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.

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Project description:Distinct epithelial gene expression phenotypes in childhood respiratory allergy

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lncRNA expression profiles from murine BALB/c macrophages at the extremes of the M(LPS+IFN-γ) and M(IL-4) polarized phenotypes

Project description:Macrophages possess the hallmark feature of plasticity, allowing them to undergo a dynamic transition between M(LPS+IFN-γ) and M(IL-4) polarized phenotypes. The aim of the present study was to screen for differentially lncRNAs that were associated with macrophage polarization. The lncRNA profiles of three M(LPS+IFN-γ) and three M(IL-4) samples were obtained using microarray analysis. Based on the threshold of fold-change >2.0 and a p-value < 0.05, we screened a total of 1,251 lncRNAs, of which 627 were upregulated and 624 downregulated in M(LPS+IFN-γ) macrophages compared to that in M(IL-4) macrophages.This study provides new insights into the role of genes in macrophage differentiation and polarization.

2020-05-19 | GSE125510 | GEO

Adults with Systemic Lupus Exhibit Distinct Molecular Phenotypes Associated with Clinical Disease Activity

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Single-cell RNA-sequencing resolves IL-4 and IFN-γ into distinct inflammatory trajectories within GM-CSF macrophages

Project description:To account for the within-state heterogeneity of GM-CSF compared to M-CSF macrophages (Helft et al. 2015), we performed multiplexed scRNA-seq on 49,441 GM-CSF–derived macrophages stimulated with IL‑4, IFN‑γ, IL‑10, or TGF‑β. Cells were visualized by principal component analysis (PC1 = 13.21%, PC2 = 4.65%), which recapitulated patterns previously observed in bulk RNA-seq. IL‑4 displaced cells farthest along PC1 towards a cell cluster enriched for NfkB controlled gene expression with high Ccl22 and Ccr7, consistent with a dendritic‑cell‑like, T‑cell‑activating phenotype. IFN‑γ dominated PC2, retaining high MHC-II expression while adding a complement/interferon module (C1qb, C1qc, Gbp2, Irf1), and showed enrichment for IRF1/8 and STAT1 transcription factor signatures. TGF‑β and IL‑10 co-clustered in the PC1/PC2 low quadrant and shared expression of reparative markers including Chil3 and Cd24, forming an immunosuppressive, trophic branch distinct from either inflammatory pole. Together, these data show that within the GM-CSF lineage, IL‑4 and IFN‑γ drive orthogonal inflammatory trajectories, whereas IL‑10 and TGF‑β consolidate a shared remodeling program.

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Bone marrow-derived macrophages express distinct transcriptional programs when activated by LPS, IFN-gamma and PAO.

Project description:mRNA microarray analysis of bone marrow derived macrophages treated under four conditions, including Naïve (N). Bone marrow derived macrophages (BMDM) were derived from the bone marrow of mice and cultured in the presence of PAO, IFN-gamma, or lipopolysaccharide (LPS). Profiled groups include Naive, LPS, IFN, PAO. Compared each of the groups (PAO, LPS, IFN) with Naïve group.

2013-08-08 | E-GEOD-48609 | biostudies-arrayexpress

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Project description:SHOW-Me

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