Background Acknowledging the importance of type I interferon (IFN) in Systemic Lupus Erythematosus (SLE), we asked if RNA containing immune complexes (RNA-IC), which trigger the IFN-α synthesis by plasmacytoid dendritic cells (pDCs), also activate type III IFN (IFN-λ1-3) production, and how this is regulated.
Methods Peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients and healthy individuals and depleted of monocytes. Immune cells were isolated from healthy PBMCs. Cells were stimulated with RNA-IC. Cytokines were measured by immunoassays, a microarray of pDCs, NK and B cells, as well as single-cell RNA-sequencing of pDCs was performed.
Results Type III IFN mRNA was induced in RNA-IC stimulated pDC-NK and pDC-B cell co-cultures, type III IFN was produced in pDC and pDC-NK cell co-culture supernatants. A small subset (3%) of RNA-IC activated pDCs expressed both IFNs type III and type I. Priming with IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF) significantly enhanced IFN-λ1/3 production by 2–5 fold. In pDC-NK cell co-cultures from SLE patients, IFN-α2b and GM-CSF increased the proportion of RNA-IC responding IFN-λ1/3 producing individuals from 9% to 36%. Hydroxychloroquine as well as an interleukin receptor 1 associated kinase 4 inhibitor (IRAK4i) significantly inhibited the RNA-IC-triggered IFN-λ1/3 production by pDCs and pDC-NK cell co-cultures by >90%.
Conclusions Type III IFN production in a small subset of pDCs can be triggered by RNA containing IC, enhanced by NK cells and several pro-inflammatory cytokines, and inhibited by blocking the TLR-MyD88 pathway, resembling the regulation of type I IFN. Thus, our results support a contributing role for both type I and type III IFN in SLE, which needs to be considered when targeting the IFN system in this disease.
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