Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

Fox, Lindsey E; Locke, Marissa C.; Lenschow, Deborah J.

doi:10.3389/fimmu.2020.606874

Cited by 21 publications

(18 citation statements)

References 349 publications

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“…IFN-ω shares ∼60% amino acid similarity to IFN-α, the type I IFN more phylogenetically close; in humans only one IFN-ω is produced compared to the 13 IFN-α subtypes ( 30 ). Intriguingly, IFN-ω is still diversifying in many species, including bats and pigs and protect them from excessive tissue damage following infection by several viruses, including Coronaviridae and Orthomixoviridae that can cause severe diseases in humans ( 30 , 31 ). Further data are needed to confirm IFN-ω induction in respiratory mucosal cells and its possible role as an anti-SARS-CoV-2 weapon in our innate responses.…”

Section: Discussionmentioning

confidence: 99%

Comparison by Age of the Local Interferon Response to SARS-CoV-2 Suggests a Role for IFN-ε and -ω

et al. 2022

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Children generally develop a mild disease after SARS-CoV-2 infection whereas older adults are at risk of developing severe COVID-19. Recent transcriptomic analysis showed pre-activated innate immunity in children, resulting in a more effective anti-SARS-CoV-2 response upon infection. To further characterize age-related differences, we studied type I and III interferon (IFN) response in SARS-CoV-2 infected and non-infected individuals of different ages. Specifically, levels of expression of type I (IFN-α, -β, -ε and -ω), type III (IFN-λ1, -λ2 and -λ3) IFNs and of the IFN-stimulated genes, ISG15 and ISG56 were quantified in nasopharyngeal cells from diagnostic swabs. Basal transcription of type I/III IFN genes was highest among children and decreased with age. Among SARS-CoV-2-infected individuals, only IFN-ε and -ω levels were significantly higher in children and young adults whereas ISGs were overexpressed in infected adults. The occurrence of symptoms in children and the need for hospitalization in adults were associated to higher transcription of several IFN genes. Starting from a pre-activated transcription level, the expression of type I and III IFNs was not highly up-regulated in children upon SARS-CoV-2 infection; young adults activated IFNs’ transcription at intermediate levels whereas older adults were characterized by higher ISGs and lower IFN-ε and -ω relative expression levels. Overall, our findings contribute to recognize components of a protective IFN response as a function of age, in the context of SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Comparison by Age of the Local Interferon Response to SARS-CoV-2 Suggests a Role for IFN-ε and -ω

et al. 2022

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“…While all IFN-I share the same components of the canonical signalling pathway, they bind to the receptor with different kinetics and affinities [ 77 , 78 ]. It is conceivable that this could result in differences in downstream kinase activation and IFN-I-subtype specific responses [ 79 ]. Our studies also identified a number of novel phosphosites in the canonical IFN-I signaling molecules STAT1 and IRF9.…”

Section: Discussionmentioning

confidence: 99%

A novel phosphoproteomic landscape evoked in response to type I interferon in the brain and in glial cells

Viengkhou

White

Cordwell

et al. 2021

J Neuroinflammation

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Background Type I interferons (IFN-I) are key responders to central nervous system infection and injury and are also increased in common neurodegenerative diseases. Their effects are primarily mediated via transcriptional regulation of several hundred interferon-regulated genes. In addition, IFN-I activate several kinases including members of the MAPK and PI3K families. Yet, how changes to the global protein phosphoproteome contribute to the cellular response to IFN-I is unknown. Methods The cerebral phosphoproteome of mice with brain-targeted chronic production of the IFN-I, IFN-α, was obtained. Changes in phosphorylation were analyzed by ontology and pathway analysis and kinase enrichment predictions. These were verified by phenotypic analysis, immunohistochemistry and immunoblots. In addition, primary murine microglia and astrocytes, the brain's primary IFN-I-responding cells, were acutely treated with IFN-α and the global phosphoproteome was similarly analyzed. Results We identified widespread protein phosphorylation as a novel mechanism by which IFN-I mediate their effects. In our mouse model for IFN-I-induced neurodegeneration, protein phosphorylation, rather than the proteome, aligned with the clinical hallmarks and pathological outcome, including impaired development, motor dysfunction and seizures. In vitro experiments revealed extensive and rapid IFN-I-induced protein phosphorylation in microglia and astrocytes. Response to acute IFN-I stimulation was independent of gene expression and mediated by a small number of kinase families. The changes in the phosphoproteome affected a diverse range of cellular processes and functional analysis suggested that this response induced an immediate reactive state and prepared cells for subsequent transcriptional responses. Conclusions Our studies reveal a hitherto unappreciated role for changes in the protein phosphorylation landscape in cellular responses to IFN-I and thus provide insights for novel diagnostic and therapeutic strategies for neurological diseases caused by IFN-I.

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“…In HNSCC, IFNα has the function of immune regulation and inhibition of tumour cell proliferation [ 227 ]. On the one hand, IFNα can resist expansion and induce apoptosis and can also activate autophagy in human nasopharyngeal carcinoma cells.…”

Section: Therapy Options In Hnsccmentioning

confidence: 99%

Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

et al. 2023

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Head and neck cancer is a malignant tumour with a high mortality rate characterized by late diagnosis, high recurrence and metastasis rates, and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer. Various factors are involved in the occurrence and development of HNSCC, including external inflammatory stimuli and oncogenic viral infections. In recent years, studies on the regulation of cell death have provided new insights into the biology and therapeutic response of HNSCC, such as apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and recently the newly discovered cuproptosis. We explored how various cell deaths act as a unique defence mechanism against cancer emergence and how they can be exploited to inhibit tumorigenesis and progression, thus introducing regulatory cell death (RCD) as a novel strategy for tumour therapy. In contrast to accidental cell death, RCD is controlled by specific signal transduction pathways, including TP53 signalling, KRAS signalling, NOTCH signalling, hypoxia signalling, and metabolic reprogramming. In this review, we describe the molecular mechanisms of nonapoptotic RCD and its relationship to HNSCC and discuss the crosstalk between relevant signalling pathways in HNSCC cells. We also highlight novel approaches to tumour elimination through RCD.

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Context Is Key: Delineating the Unique Functions of IFNα and IFNβ in Disease

Cited by 21 publications

References 349 publications

Comparison by Age of the Local Interferon Response to SARS-CoV-2 Suggests a Role for IFN-ε and -ω

Comparison by Age of the Local Interferon Response to SARS-CoV-2 Suggests a Role for IFN-ε and -ω

A novel phosphoproteomic landscape evoked in response to type I interferon in the brain and in glial cells

Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

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