Abstract
BackgroundIn systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. We asked how an interleukin (IL)-1 receptor-associated kinase 4 small molecule inhibitor (IRAK4i) affects RNA-IC-induced cytokine production compared with hydroxychloroquine (HCQ).MethodsPlasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy individuals. PBMCs from SLE patients and healthy individuals were depleted of monocytes. Cells were stimulated with RNA-containing IC (RNA-IC) in the presence or absence of IRAK4i I92 or HCQ, and cytokines were measured by immunoassay or flow cytometry. Transcriptome sequencing was performed on RNA-IC-stimulated pDCs from healthy individuals to assess the effect of IRAK4i and HCQ.ResultsIn healthy individuals, RNA-IC induced interferon (IFN)-α, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-γ, macrophage inflammatory protein (MIP)1-α, and MIP1-β production in pDC and NK cell cocultures. IFN-α production was selective for pDCs, whereas both pDCs and NK cells produced TNF-α. IRAK4i reduced the pDC and NK cell-derived cytokine production by 74–95%. HCQ interfered with cytokine production in pDCs but not in NK cells. In monocyte-depleted PBMCs, IRAK4i blocked cytokine production more efficiently than HCQ. Following RNA-IC activation of pDCs, 975 differentially expressed genes were observed (false discovery rate (FDR) < 0.05), with many connected to cytokine pathways, cell regulation, and apoptosis. IRAK4i altered the expression of a larger number of RNA-IC-induced genes than did HCQ (492 versus 65 genes).ConclusionsThe IRAK4i I92 exhibits a broader inhibitory effect than HCQ on proinflammatory pathways triggered by RNA-IC, suggesting IRAK4 inhibition as a therapeutic option in SLE.
Highlights
In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells
IRAK4 inhibition reduces proinflammatory cytokine production by activated pDCs and NK cells more extensively than HCQ To investigate whether IRAK4 inhibition affects production of other proinflammatory cytokines, levels of IL-6, Fig. 1 Regulatory effect of hydroxychloroquine (HCQ) and the interleukin-1 receptor associated kinase 4 inhibitor (IRAK4i) I92 on tumor necrosis factor (TNF)-α and interferon (IFN)-α production. a–d Cocultures of plasmacytoid dendritic cells and natural killer (NK) cells from healthy donors were stimulated with RNA-containing immune complexes (RNA-IC) for 5 h (a,b) or 9 h (c,d) in the absence or presence of HCQ or I92
IRAK4 inhibition blocks production of proinflammatory cytokines by Peripheral blood mononuclear cell (PBMC) from SLE patients As healthy individuals and SLE patients may respond differently, we investigated if cytokine production in cells from patients with SLE could be targeted with an IRAK4i
Summary
In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. One important event is the induction of type I IFN production by plasmacytoid dendritic cells (pDCs) in response to ICs consisting of autoantibodies and apoptotic or necrotic cell-derived nucleic acids [3]. Such interferogenic ICs are internalized in pDCs via fragment crystallizable receptor IIA (FcγRIIA) and directed to the endosomes, where RNA and DNA interact with Toll-like receptor (TLR) and 9, respectively [4]. The final outcome in SLE is a complex inflammatory response that is difficult to bring into complete remission
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