Interferonopathy Resulting from Dysregulation of Interferon Production

Abstract

This commentary, prepared for the Howard Young Festschrift, recognizes Howard for his many contributions to the interferon (IFN) and cytokine community. Howard Young has spent his professional career as an investigator at the National Cancer Institute (NCI). He presently is a senior investigator in the Laboratory of Cancer Immunometabolism, Center for Cancer Research, NCI.

Howard's scholarly research for many years has focused on the regulation of cytokine gene expression with emphasis on the IFNs, principally type II or gamma IFN (IFNγ) (Young 2006; Savan and others 2009; Lin and Young 2014; Burke and others 2016; Fenimore and Young, 2016; Green and others 2017). Among the accomplishments of the Young laboratory is the development of a mouse model characterized by chronic IFNγ expression, which they showed results in autoimmune disease (Hodge and others 2014; Lin and others 2014; Bae and others 2016).

IFN, a cornerstone of innate immunity, was discovered based on its antiviral activity during studies of viral interference (Isaacs and Lindenmann 1957). Influenza virus-infected cells produced a secreted soluble factor that possessed antiviral activity against both homologous influenza virus and heterologous viruses. Subsequent studies established that IFN actually is a multigene family that includes type I or viral IFNs (α, β), type II or immune IFN (γ), and type III or lambda IFN (λ). IFNs display a range of biological activities in addition to their hallmark antiviral activity, including the triggering of autoimmune disorders.

Dysregulation of IFN expression leading to IFN over production can result in interferonopathies. This was shown by Howard's laboratory in their studies of IFNγ in the mouse (Hodge and others 2014; Bae and others 2016). The Young laboratory generated a homozygous null mouse with a 162 nt AU-rich element deleted from the 3’-untranslated region of the IFNγ transcript (Hodge and others 2014). This deletion created a mouse model with chronic circulating IFNγ that developed autoimmunity, displaying phenotypic characteristics of systemic lupus erythematosus. Heterozygotic IFNγ AU element deletion mice developed no or only mild autoimmunity.

Research by my laboratory has largely focused on antiviral mechanisms of type I IFN action (Samuel 2001) and the roles played by 2 double-stranded RNA (dsRNA)-binding enzymes, the protein kinase PKR (Samuel 1993; Pfaller and others 2011) and the adenosine (A) to inosine (I) RNA editing enzyme now known as adenosine deaminase acting on RNA1 (ADAR1) (Samuel 2019; Pfaller and others 2021). We found that expression of the Adar1 gene is regulated by alternative promoters and exon 1 splicing in a manner that gives rise to 2 size isoforms of ADAR1, p150 that is IFN inducible and p110 that is constitutively expressed (Patterson and Samuel 1995; George and Samuel, 1999; Ward and others 2011).

Subsequent studies by multiple laboratories established using the mouse model that deficiency of Adar1 results in enhanced type I IFN production mediated by melanoma differentiation associated gene 5 protein (MDA5)-dependent retinoic acid-inducible gene I (RIG) signaling (Hartner and others 2009; Liddicoat and others 2015; Pestal and others 2015); embryonic lethality (Hartner and others 2009; Ward and others 2011; Liddicoat and others 2015; Pestal and others 2015); and enhanced activation of dsRNA-dependent responses including those illustrated by PKR and oligoadenylate synthetase-RNase L in addition to MDA5 (Toth and others 2009; Liddicoat and others 2015; Pestal and others 2015; George and others 2016; Samuel 2019).

ADAR1 p150 acts to suppress innate immune responses including MDA5-dependent induction of IFN and activation of PKR (Hartner and others 2009; Toth and others 2009; Rice and others 2012; Liddicoat and others 2015; Pestal and others 2015; George and others 2016). A model summarizing the role of ADAR1 as a suppressor of dsRNA-triggered innate immune responses is shown in Fig. 1.

FIG. 1.

Model by which ADAR1 p150 acts to suppress innate immune responses dependent upon dsRNA. Cytoplasmic RIG-like receptors (RLR, MDA5, and RIG-I) and endosome-associated TLR3 sense dsRNA and signal through adapters (MAVS and TRIF) to activate IRF and NF-κB factors that transcriptionally induce IFN expression. Among the ISGs induced by JAK-STAT signaling are the Pkr, the Oas, and the p150 Adar1. PKR and OAS are dsRNA-activated enzymes. PKR, when activated by dsRNA-dependent autophosphorylation, catalyzes the phosphorylation of serine 51 of translation initiation factor eIF2α, thereby leading to an inhibition of translation initiation. OAS, when activated by dsRNA, catalyze the synthesis of 2’-5’-oligoadenylates (2-5A) that activate the RNase L, thereby leading to RNA degradation. Cells deficient of the IFN-inducible p150 isoform of ADAR1 accumulate viral (nonself) and cellular (self) dsRNAs above the threshold concentration required for activation of dsRNA-dependent innate immune sensors including MDA5, PKR, and OAS, thereby leading to IFN production and action. In IFN-treated cells, cytoplasmic p150 ADAR1 is induced, thereby leading to A-to-I RNA editing and inactivation of cellular (self) dsRNAs by C6-adenosine deamination. The intracellular dsRNA concentration then presumably falls below the threshold required for innate sensor activation. Viral infection may lead to an increased concentration of viral (nonself) dsRNA that surpasses the threshold level for dsRNA sensor activation and hence triggering of dsRNA-dependent innate immune responses. (From Samuel 2019 in adapted form). ADAR1, adenosine deaminase acting on RNA 1; dsRNA, double-stranded RNA; RNase L, endoribonuclease L; IFN, interferon; ISGs, IFN-stimulated genes; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation associated gene 5 protein; OAS, oligoadenylate synthetase; PKR, protein kinase R; RIG-I, retinoic acid-inducible gene I; RLR, RIG-like receptors; TLR3, Toll-like receptor 3; TRIF, TIR-domain-containing adapter-inducing interferon-β.

Deficiency of catalytically active p150 ADAR1 results in chronic elevated production and action of type I IFN in uninfected cells and in some instances also virus-infected cells, resulting in an interferonopathy (Hartner and others 2009; Toth and others 2009; Rice and others 2012; George and others 2016). As Howard Young's laboratory established, chronic elevated type II IFN expression can result in autoimmune disease (Hodge and others 2014; Lin and others 2014; Bae and others 2016). Hence, interferonopathies may arise after dysregulation of either type I or type II IFN.

In addition to Howard Young's scholarly contributions, his exceptional service to our professional community is especially noteworthy. Howard served as president of the International Society for Interferon and Cytokine Research (ISICR) in 2004–2005. He has edited the society's Signals Newsletter since its inception. He has served for several years as an associate editor of the Journal of Interferon and Cytokine Research. In recognition of his many contributions, Howard received the Honorary Lifetime Membership Award of the International Cytokine and Interferon Society (ICIS) in 2016. And, he was the first recipient of the ICIS Mentorship Award in 2021.

I had the privilege to work together with Howard Young while serving as president of ISICR during the ISICR and ICS merger process and then as founding copresident with Luke O'Niell of our newly formed ICIS Society. Howard is a wonderful person and contributor of the highest order. He has combined a fine research career at NCI with an impressive record of service to the IFN and cytokine community.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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