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Status |
Public on May 23, 2020 |
Title |
The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells [microarray] |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by array
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Summary |
Objective: Patients with Systemic Lupus Erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III interferon (IFN) in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC, and how this production can be regulated. Methods: Peripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA-sequencing of pDCs using ddSEQ technology was performed. Results: Type III IFN mRNA and protein was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 or granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2-5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p<0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%. Conclusions: Type III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
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Overall design |
RNA was isolated after 6 hours treatment of cells from two healthy individuals with RNA-IC or medium (mock).
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Contributor(s) |
Hjorton K, Hagberg N, Pucholt P, Eloranta M, Rönnblom L |
Citation(s) |
32503683 |
Submission date |
Apr 27, 2020 |
Last update date |
Jun 16, 2020 |
Contact name |
Pascal Pucholt |
E-mail(s) |
pascal.pucholt@medsci.uu.se
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Organization name |
Uppsala University
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Department |
Medical Science
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Lab |
Rheumatology
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Street address |
Dag Hammarskjölds väg 20
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City |
Uppsala |
ZIP/Postal code |
751 23 |
Country |
Sweden |
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Platforms (1) |
GPL13607 |
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Feature Number version) |
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Samples (20)
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This SubSeries is part of SuperSeries: |
GSE149456 |
The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells |
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Relations |
BioProject |
PRJNA628646 |