Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes

Ng, Cherie; Mendoza, Juan L.; García, K. Christopher; Oldstone, Michael B. A.

doi:10.1016/j.cell.2015.12.027

Cited by 116 publications

(85 citation statements)

References 31 publications

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“…This work supports an immune-stimulating, antiviral role for IFN-α as opposed to an immunosuppressive effect by IFN-β (328, 331, 332). IFN-β specifically inhibits antiviral T-cell responses and promotes viral persistence (331). In contrast, IFN-α-signaling associates with tissue damage and antiviral activity (331, 332).…”

Section: Interactions Between T1-ifns and Th17 Immunity In Tbsupporting

confidence: 74%

“…Recently, these different immunoregulatory roles of IFN-α and IFN-β in SLE and MS have been confirmed by more detailed analysis of blood transcriptional profiles in patients (330). The molecular explanation for the differential function of IFN-α and IFN-β traces back to subtle differences in receptor binding, signaling cascades, and feedback mechanisms initiated and has been reviewed in detail elsewhere (28, 331). …”

Section: Interactions Between T1-ifns and Th17 Immunity In Tbmentioning

confidence: 99%

“…IFN-β specifically inhibits antiviral T-cell responses and promotes viral persistence (331). In contrast, IFN-α-signaling associates with tissue damage and antiviral activity (331, 332). …”

Section: Interactions Between T1-ifns and Th17 Immunity In Tbmentioning

confidence: 99%

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Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

et al. 2017

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The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research.

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Section: Interactions Between T1-ifns and Th17 Immunity In Tbsupporting

confidence: 74%

Section: Interactions Between T1-ifns and Th17 Immunity In Tbmentioning

confidence: 99%

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Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

et al. 2017

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“…aureus skin infections in patients undergoing treatment with these EGFR inhibitors [8, 58]. Mounting evidence actually indicates that type I IFNs can exert a deleterious effect in bacterial infections [16, 59], and may be involved in harmful rather than beneficial functions [60]. For instance, type I IFNs are considered crucially implicated in the increased susceptibility to post-influenza Staph.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

2016

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The Epidermal Growth Factor Receptor (EGFR) is centrally involved in the regulation of key processes of the epithelia, including cell proliferation, survival, differentiation, and also tumorigenesis. Humanized antibodies and small-molecule inhibitors targeting EGFR were developed to disrupt these functions in cancer cells and are currently used in the treatment of diverse metastatic epithelial cancers. By contrast, these drugs possess significant skin-specific toxic effects, comprising the establishment of a persistent inflammatory milieu. So far, the molecular mechanisms underlying these epiphenomena have been investigated rather poorly. Here we showed that keratinocytes respond to anti-EGFR drugs with the development of a type I interferon molecular signature. Upregulation of the transcription factor IRF1 is early implicated in the enhanced expression of interferon-kappa, leading to persistent activation of STAT1 and further amplification of downstream interferon-induced genes, including anti-viral effectors and chemokines. When anti-EGFR drugs are associated to TNF-α, whose expression is enhanced by the drugs themselves, all these molecular events undergo a dramatic enhancement by synergy mechanisms. Finally, high levels of interferon-kappa can be observed in epidermal keratinocytes and also in leukocytes infiltrating the upper dermis of cetuximab-driven skin lesions. Our data suggest that dysregulated activation of type I interferon innate immunity is implicated in the molecular processes triggered by anti-EGFR drugs and leading to persistent skin inflammation.

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“…3A). However, heterogeneity in the antiviral properties of different type I and type III IFN variants has been reported with respect to other viruses (59,60). To compare efficacies of alternative type I and type III IFNs, HIEs were pretreated with IFN-λ3 (type III IFN) or IFN-α2 (type I IFN) and compared with their analogs, IFN-λ1 and IFN-β1, respectively.…”

Section: Exogenous Ifn Treatment Restricts Rotavirus Growth In Hiesmentioning

confidence: 99%

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

Saxena

Simon

Zeng

et al. 2017

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

112

150

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The intestinal epithelium can limit enteric pathogens by producing antiviral cytokines, such as IFNs. Type I IFN (IFN-α/β) and type III IFN (IFN-λ) function at the epithelial level, and their respective efficacies depend on the specific pathogen and site of infection. However, the roles of type I and type III IFN in restricting human enteric viruses are poorly characterized as a result of the difficulties in cultivating these viruses in vitro and directly obtaining control and infected small intestinal human tissue. We infected nontransformed human intestinal enteroid cultures from multiple individuals with human rotavirus (HRV) and assessed the host epithelial response by using RNAsequencing and functional assays. The dominant transcriptional pathway induced by HRV infection is a type III IFN-regulated response. Early after HRV infection, low levels of type III IFN protein activate IFN-stimulated genes. However, this endogenous response does not restrict HRV replication because replication-competent HRV antagonizes the type III IFN response at pre-and posttranscriptional levels. In contrast, exogenous IFN treatment restricts HRV replication, with type I IFN being more potent than type III IFN, suggesting that extraepithelial sources of type I IFN may be the critical IFN for limiting enteric virus replication in the human intestine.enteric virus | interferon | human enteroids | human rotavirus T he human small intestinal epithelium is the primary site of infection and replication for many gastrointestinal pathogens. However, fundamental knowledge about intestinal epithelial cellpathogen interactions in humans is limited as a result of the impracticality of studying these cells in vivo. Modeling these interactions in vitro is difficult because many human enteric pathogens fail to replicate or replicate poorly in cancer cell lines derived primarily from the human colon (1-4). Human intestinal enteroids (HIEs) represent a new in vitro model of the human small intestinal epithelium; this model was developed following advances in stem cell biology, and it recapitulates many of the biological and physiological properties of the human small intestine in vivo (5, 6). Unlike other in vitro models, HIEs are easily established from nontransformed small intestinal tissue, can be maintained on a long-term basis, and contain a stem cell niche and the diversity of intestinal epithelial cell types (enterocytes, goblet, enteroendocrine, and Paneth cells) present in vivo (6, 7). HIEs allow for comparisons of intestinal host responses across genetically diverse individuals (8) and reproduce many of the in vivo pathophysiological properties of infection by a human enteric viral pathogen, human rotavirus (HRV) (9).HRVs are the major etiology of severe diarrhea in children under the age of 5 y worldwide, resulting in an estimated 215,000 deaths annually (10). HRVs replicate to high titers in humans but replicate poorly or not at all in small animal models (11,12). This host restriction of HRV in animal models is based on properties o...

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Alpha and Beta Type 1 Interferon Signaling: Passage for Diverse Biologic Outcomes

Abstract: Summary Type I interferon (IFN-I) elicits a complex cascade of events in response to microbial infection. Here, we review recent developments illuminating the large number of IFN-I species and describing their unique biologic functions.

Cited by 116 publications

References 31 publications

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

A paradox of transcriptional and functional innate interferon responses of human intestinal enteroids to enteric virus infection

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