Expression of Long Interspersed Nuclear Element 1 Retroelements and Induction of Type I Interferon in Patients With Systemic Autoimmune Disease

Abstract

Objective Increased type I interferon (IFN-I) and a broad signature of IFN-I-induced gene transcripts are observed in patients with SLE and other systemic autoimmune diseases. To identify disease-relevant triggers of the IFN-I pathway we investigated whether endogenous virus-like genomic repeat elements, normally silent, might be expressed in patients with systemic autoimmune disease, activate an innate immune response and induce IFN-I. Methods Expression of IFN-I and long interspersed nuclear element-1 (LINE-1; L1) was studied in kidney tissue from lupus patients and minor salivary gland (MSG) tissue from patients with primary Sjogren’s syndrome (SS) by PCR, western blot and immunohistochemistry. Induction of IFN-I by L1 was investigated by transfection of plasmacytoid dendritic cells (pDCs) or monocytes with an L1-encoding plasmid or L1 RNA. Involvement of innate immune pathways and altered L1 methylation were assessed. Results L1 mRNA transcripts were increased in lupus nephritis kidneys and in MSG from SS patients and correlated with IFN-I expression and L1 DNA demethylation. L1 open reading frame 1/p40 protein and IFNβ were expressed in MSG ductal epithelial cells and in lupus kidneys, and IFNα was detected in infiltrating pDCs. Transfection of pDCs or monocytes with L1-encoding DNA or RNA induced IFN-I. Inhibition of TLR7/8 reduced L1 induction of IFNα in pDCs and an inhibitor of IKKε/TBK1 abrogated induction of IFN-I by L1 RNA in monocytes. Conclusion L1 genomic repeat elements represent endogenous nucleic acid triggers of the IFN-I pathway in SLE and SS and may contribute to initiation or amplification of autoimmune disease.

DNA methylation alterations in the pathogenesis of lupus

“…Mavraga et al . found that LINE‐1 mRNA transcripts increased in lupus nephritis kidneys and minor salivary gland tissue from Sjögren's syndrome patients are correlated with its DNA demethylation and type I IFN expression . Recently, Coit et al .…”

Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies

“…In addition, hypomethylation of transposon LINE1 has been also found in SLE neutrophils consistent with global hypomethylation. Indeed, increased expression of LINE1 is associated with increased type I interferon production and has been described in SLE [28, 29]. …”

Editorial: LINEing Up to Boost Interferon Production: Activation of Endogenous Retroviral DNA in Autoimmunity

“…Moreover, mitochondrial oxidative stress activates the mitochondrial antiviral signaling protein (MAVS), which acts as an amplifier of RIG‐1 activation during IFN signaling . Oxidative stress also causes DNA hypomethylation , a process that underlies increased LINE‐1 expression . In addition to promoting nucleic acid–driven IFN production, ERV Gag‐encoded proteins, such as HRES‐1/p28, or the LINE‐1 p40 protein may also contribute to autoimmunity via molecular mimicry .…”

“…In this issue of Arthritis & Rheumatology , Mavragani and colleagues demonstrate that the transcription of LINE‐1 is increased in kidney tissue from patients with lupus nephritis and in minor salivary gland (MSG) tissue from patients with SS, and that increased LINE‐1 transcription correlates with greater expression of type I IFN . LINE‐1 ORF‐1/p40 protein and IFNβ are also highly expressed in MSG ductal epithelial cells and in lupus kidneys, and IFNα is detected in infiltrating plasmacytoid dendritic cells (PDCs).…”

“…Since Mavragani et al also demonstrated that methylation of CpG sites in the LINE‐1 promoter are negatively correlated with LINE‐1 expression in MSG tissue , it is likely that demethylation may play a critical role in the observed overexpression of LINE‐1. Interestingly, LINE‐1 transcription via hypomethylation is readily induced by oxidative stress, and it responds to treatment with the antioxidant N ‐acetylcysteine (NAC) .…”