Pharmacological Inhibition of Type I Interferon Signaling Protects Mice Against Lethal Sepsis

Dejager, Lien; Vandevyver, Sofie; Ballegeer, Marlies; Wonterghem, Elien Van; An, Ling–Ling; Riggs, Jeffrey M.; Kolbeck, Roland; Libert, Claude

doi:10.1093/infdis/jit600

Cited by 48 publications

(40 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These findings suggest that the subset of genes induced by signaling through the IFN-αR1 chain alone, independent of the IFN-αR2 chain, contribute more substantially to the pathogenesis of Gram-negative endotoxemia than the classical ISGs induced by signaling through conventional IFN-αR1/IFN-αR2 heterodimeric complexes. Furthermore, related studies by others showed that treatment with a neutralizing anti-IFN-αR1 mAb protects mice against development of endotoxin-induced lethality in 2 distinct murine models of Gram-negative septicemia [44]. Together, these studies suggest that blocking signaling through the IFN-αR1 chain, but not the IFN-αR2 chain, provides a useful therapeutic approach to the treatment of bacterial endotoxemia.…”

Section: Discussionmentioning

confidence: 97%

An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages

Sheikh

Dickensheets

Gamero

et al. 2014

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 97%

An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages

Sheikh

Dickensheets

Gamero

et al. 2014

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

“…Detrimental roles for IFN-␤ and/or its receptor IFNAR1 have been described during sepsis (15)(16)(17), bacterial infections including Listeria and Mycobacterium spp. (18), parasitic infections caused by Trypanosoma and Leishmania spp.…”

Section: Discussionmentioning

confidence: 99%

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Weerd

Matthews

Pattie

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Luke O'NeillThe interaction of IFN-␤ with its receptor IFNAR1 (interferon ␣/␤ receptor subunit 1) is vital for host-protective anti-viral and anti-proliferative responses, but signaling via this interaction can be detrimental if dysregulated. Whereas it is established that IFNAR1 is an essential component of the IFNAR signaling complex, the key residues underpinning the IFN-␤-IFNAR1 interaction are unknown. Guided by the crystal structure of the IFN-␤-IFNAR1 complex, we used truncation variants and site-directed mutagenesis to investigate domains and residues enabling complexation of IFN-␤ to IFNAR1. We have identified an interface on IFNAR1-subdomain-3 that is differentially utilized by IFN-␤ and IFN-␣ for signal transduction. We used surface plasmon resonance and cell-based assays to investigate this important IFN-␤ binding interface that is centered on IFNAR1 residues Tyr 240 and Tyr The type I IFNs, including 14 IFN-␣ and lone IFN-␤, IFN-⑀, and IFN-, have critical roles in response to viral and bacterial infections and cancers (1, 2). They are also applied clinically for the treatment of hepatitis virus B and C (1), cancers including melanoma (3), and multiple sclerosis (4). Although they show clinical efficacy, their use is restricted by dose-limiting toxicities, including leukopenia, nausea, fatigue, neurological disorders (3), and localized cutaneous effects (5). All type I IFNs engage their cognate receptors, IFNAR1 and IFNAR2, to activate the canonical JAK-STAT signaling pathway, but ligand engagement can also activate alternative signaling pathways (6). Despite sharing these receptor components, there are IFN subtype-specific elements to signaling; compared with IFN-␣, IFN-␤ has specific roles in osteoclastogenesis (7), control of chronic viral infection (8), the potent induction of apoptotic pathways required for control of tumor cell growth, and the development of B cells and myelopoiesis (9).Structural insight into the IFN-IFNAR 5 interactions has been gleaned from the crystal structures of a human IFN-␣2 variant and human IFN-in complex with both IFNAR1 and IFNAR2 (10). Furthermore, specific insight into the mode of IFN-␤-mediated activation of IFNAR1 was obtained from the crystal structure of the murine IFN-␤-IFNAR1 complex (11). Comparison of these structures and evidence from the literature (12) suggests that the minimal ligand binding domains for human and mouse IFNAR1 are similar and sit broadly across the three membrane distal SDs (SD1-3) of the receptor with limited involvement of the membrane proximal subdomain, SD4 (Fig. 1A). It has also been shown that key residues discriminate between ligands and that there is potential for ligand-specific interaction interfaces (10, 11).

show abstract

“…Puerperal sepsis, a bacterial infection originating in the uterus following delivery, is the leading infectious cause of maternal death worldwide (26). Type I IFN signaling has been associated with increased severity of infection with a number of relevant pathogens, including staphylococcal and Pseudomonas species (27,28). Likewise, elevated levels of type I IFN are associated with pathogenesis of certain autoimmune diseases such as systemic lupus erythematosus (SLE) (29).…”

Section: Discussionmentioning

confidence: 99%

Prolonged activation of innate antiviral gene signature after childbirth is determined byIFNL3genotype

Price

Tedesco

Prasad

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant control subjects. Interestingly, interferon-stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14 + cells and could be stratified according to genetic variation at the interferon-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together, these data suggest that postpartum, the normalization of the physiological rheostat controlling IFN signaling depends on IFNL3 genotype. postpartum | CD14 | interferon | innate immunity | antiviral genes

show abstract

Pharmacological Inhibition of Type I Interferon Signaling Protects Mice Against Lethal Sepsis

Cited by 48 publications

References 47 publications

An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages

An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages

A hot spot on interferon α/β receptor subunit 1 (IFNAR1) underpins its interaction with interferon-β and dictates signaling

Prolonged activation of innate antiviral gene signature after childbirth is determined byIFNL3genotype

Contact Info

Product

Resources

About