Interferon pathway in SLE: one key to unlocking the mystery of the disease

Lars Rönnblom, Dag Leonard, Lars Rönnblom, Dag Leonard

Abstract

SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms. The consequences for the immune system is a continuous stimulation to an immune response, and for the patient a number of different organ manifestations leading to typical symptoms for SLE. In the current review, we will present the existing knowledge of the IFN system and pathway activation in SLE. We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.

Keywords: interferon; plasmacytoid dendritic cell; systemic lupus erythematosus.

Conflict of interest statement

Competing interests: LR has received a research grant from AstraZeneca and received honoraria for scientific advice from Biogen.

Figures

Figure 1
Figure 1
Interferon receptors and signalling. The interferons are classified into three types, which bind to distinct receptors. This induces activation of overlapping pathways resulting in expression of different genes. GAS, interferon-gamma activated sequence; IFN, interferon; IFNAR, interferon alpha receptor; IFNGR, interferon gamma receptor; IFN-λR1, interferon lambda receptor 1; IL-10Rβ, interleukin-10 receptor β; IRF, interferon regulatory factor; ISGF3, interferon-stimulated gene factor 3; ISRE, interferon-stimulated response elements; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2.
Figure 2
Figure 2
Inducers and regulators of IFN-α production by plasmacytoid dendritic cell. APC, antigen-presenting cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; IC, immune complex; IFN, interferon; IL-3, interleukin 3; LFA1, lymphocyte function–associated antigen 1; MIP-1β, macrophage inflammatory protein-1β; NET, neutrophil extracellular traps; PECAM-1, platelet and endothelial cell adhesion molecule 1; ROS, reactive oxygen species.
Figure 3
Figure 3
Schematic picture of the type I interferon production and different nucleic acid sensors. cGAMP, cyclic GMP-AMP; cGAS, cyclic GMP-AMP synthase; DAI, DNA-dependent activator of IFN-regulatory factors; DDX41, DEAD-box helicase 41; DNA-PKcs, DNA-dependent protein kinase; ER, endoplasmatic reticulum; FCGRIIA, Fc-gamma receptor II A; IC, immune complex; IFI16, gamma-interferon-inducible protein 16; IRAK, interleukin-1 receptor–associated kinase; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral-signalling protein; MDA5, melanoma differentiation–associated protein 5; MyD88, myeloid differentiation primary response 88; NET, neutrophil extracellular traps; RIG-I, retinoic acid–inducible gene I; STING, stimulator of interferon genes; TLR, Toll-like receptor; TRAF6, TNF receptor–associated factors; TREX1, three prime repair exonuclease 1.
Figure 4
Figure 4
Effect of interferons (IFNs) on different cell types. NET, neutrophil extracellular traps.

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