Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

Abstract

Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions as an antagonist, agonist, or transporter is unknown. In this study, we elucidate the in vivo importance of the soluble type I IFNAR, soluble (s)IFNAR2a, which is generated by alternative splicing of the Ifnar2 gene. A transgenic mouse model was established to mimic the 10–15-fold elevated expression of sIFNAR2a observed in some human diseases. We generated transgenic mouse lines, designated SolOX, in which the transgene mRNA and protein-expression patterns mirrored the expression patterns of the endogenous gene. SolOX were demonstrated to be more susceptible to LPS-mediated septic shock, a disease model in which type I IFN plays a crucial role. This effect was independent of “classical” proinflammatory cytokines, such as TNF-α and IL-6, whose levels were unchanged. Because the increased levels of sIFNAR2a did not affect the kinetics of the increased interferonemia, this soluble receptor does not potentiate its ligand signaling by improving IFN pharmacokinetics. Mechanistically, increased levels of sIFNAR2a are likely to facilitate IFN signaling, as demonstrated in spleen cells overexpressing sIFNAR2a, which displayed quicker, higher, and more sustained activation of STAT1 and STAT3. Thus, the soluble IFNR is an important agonist of endogenous IFN actions in pathophysiological processes and also is likely to modulate the therapeutic efficacy of clinically administered IFNs.

A Cytoplasmic RNA Virus Alters the Function of the Cell Splicing Protein SRSF2

“…Epstein-Barr virus (EBV) itself encodes a splicing factor, SM, that influences splicing and processing of host pre-mRNAs (54,55). Splice variants, including those that encode dominant negative proteins, have been described for several genes involved in the IFN-␣/␤ response (56)(57)(58)(59)(60)(61)(62)(63). Notably, the EBV SM protein skews the mRNA splicing patterns of STAT1, enhancing production of the dominant-negative STAT1␤ isoform (55).…”

HIV infection does not alter Interferon α/β receptor expression on mucosal immune cells

“…Both agonistic and antagonistic properties of sIFNAR2a where shown in mice, specifically their ability to influence the efficacy of therapeutic IFNα treatment [15,53]. In mouse cell lines and primary cells overexpressing sIFNAR2a, the antiproliferative and antiviral effects of IFNα and IFNβ stimulation were inhibited.…”

Higher Serum Levels of Type I Interferon Receptor in Adults with Chronic Hepatitis B Leading to Hepatitis B Surface Antigen Clearance

“…Even though these soluble cytokine receptors have been considered as antagonists for transmembrane forms of the receptors, they also perform as carrier proteins to increase the stability of type I IFNs ligands by keeping them from proteolysis and clearance. In this way, they are agonists for modifying ligand activity in a transsignaling pathway (6,9,25,26). On the other hand, it has been demonstrated that the numbers of pDC are decreased in the IFNI-dependent proapoptotic manner in viral hepatitis (9).…”

“…Likewise, Zhao et al (24) showed that the mRNA and plasma levels of IFNAR1 and IFNAR2c were increased in CHB and liver cirrhosis patients compared with healthy controls. Soluble IF-NAR2 is an important regulator of endogenous and systemically administered of type I IFNs (9,25,26). Interferons-α/β are virus-interfering factors that involved in both immunostimulatory and immunosuppressive properties (27).…”