Abnormalities of the type I interferon signaling pathway in lupus autoimmunity. (October 2021)

• Record Type: Journal Article
• Authors: Gallucci, Stefania; Meka, Sowmya; Gamero, Ana M.
• Is Part Of: Cytokine. Volume 146(2021)
• Publication Date: 2021-10
• Subjects: Systemic Lupus Erythematosus -- Autoimmunity -- Type I interferon -- Signaling pathways -- STAT -- JAK -- GWAS -- Epigenetic; ADAR1 Adenosine deaminases acting on RNA -- Anti-RBP anti-RNA binding protein -- Anti-dsDNA anti-double-stranded DNA -- cDC Conventional Dendritic Cells -- ChIP Chromatin immunoprecipitation -- DAMPs Damage-associated molecular patterns -- DNA deoxyribonucleic acid -- EWAS Epigenome-Wide Association Studies -- GAS gamma-activated sites -- GWAS Genome Wide Association Study -- H3K4me3 Histone H3 lysine K4 (H3K4) -- IFN Interferon -- IFNAR Interferon-alpha/beta receptor -- IRF Interferon Responsive Factor -- ISGs Interferon stimulated genes -- ISGF3 Interferon-stimulated gene factor 3 -- IL-12 Interleukin 12 -- IL-23 Interleukin 23 -- ISRE IFN-stimulated response elements -- JAK Janus Kinase -- LncRNA Long non-coding RNA -- LN Lupus Nephritis -- MAPK Mitogen-activated protein kinase -- MDA5 Melanoma differentiation-associated protein 5 -- mRNA Messenger ribonucleic acid -- NF-kB Nuclear Factor Kappa B -- PAMPs Pathogen-associated molecular patterns -- PBMCs Peripheral blood mononuclear cells -- PRRs Pattern recognition receptors -- RIG-I retinoic acid inducible gene I -- RLRs RIG-I-like receptors -- RNA Ribonucleic Acid -- SAMHD1 Sterile Alpha Motif (SAM) domain- Histidine- Aspartic (HD) domain-containing protein 1 -- SNP Single Nucleotide Polymorphism -- SOCS1 Suppressor of cytokine signaling 1 -- STAT Signal transducer and activator of transcription -- STING Stimulator of interferon genes -- SLE Systemic Lupus Erythematosus -- TLRs Toll-like receptors -- TREX1 Three prime repair exonuclease -- TYK2 Tyrosine Kinase 2 -- USP18 Ubiquitin specific peptidase 18; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2021.155633
• Languages: English
• ISSNs: 1043-4666

Abstract

Abstract: Type I interferons (IFNs), mostly IFNα and IFNβ, and the type I IFN Signature are important in the pathogenesis of Systemic Lupus Erythematosus (SLE), an autoimmune chronic condition linked to inflammation. Both IFNα and IFNβ trigger a signaling cascade that, through the activation of JAK1, TYK2, STAT1 and STAT2, initiates gene transcription of IFN stimulated genes (ISGs). Noteworthy, other STAT family members and IFN Responsive Factors (IRFs) can also contribute to the activation of the IFN response. Aberrant type I IFN signaling, therefore, can exacerbate SLE by deregulated homeostasis leading to unnecessary persistence of the biological effects of type I IFNs. The etiopathogenesis of SLE is partially known and considered multifactorial. Family-based and genome wide association studies (GWAS) have identified genetic and transcriptional abnormalities in key molecules directly involved in the type I IFN signaling pathway, namely TYK2, STAT1 and STAT4, and IRF5 . Gain-of-function mutations that heighten IFNα/β production, which in turn maintains type I IFN signaling, are found in other pathologies like the interferonopathies. However, the distinctive characteristics have yet to be determined. Signaling molecules activated in response to type I IFNs are upregulated in immune cell subsets and affected tissues of SLE patients. Moreover, Type I IFNs induce chromatin remodeling leading to a state permissive to transcription, and SLE patients have increased global and gene-specific epigenetic modifications, such as hypomethylation of DNA and histone acetylation. Epigenome wide association studies (EWAS) highlight important differences between SLE patients and healthy controls in Interferon Stimulated Genes (ISGs). The combination of environmental and genetic factors may stimulate type I IFN signaling transiently and produce long-lasting detrimental effects through epigenetic alterations. Substantial evidence for the pathogenic role of type I IFNs in SLE advocates the clinical use of neutralizing anti-type I IFN receptor antibodies as a therapeutic strategy, with clinical studies already showing promising results. Current and future clinical trials will determine whether drugs targeting molecules of the type I IFN signaling pathway, like non-selective JAK inhibitors or specific TYK2 inhibitors, may benefit people living with lupus.