scholarly journals Type I interferons in host defence and inflammatory diseases

2019 ◽  
Vol 6 (1) ◽  
pp. e000336 ◽  
Author(s):  
Mary K. Crow ◽  
Lars Ronnblom
Keyword(s):  
Nucleic Acid ◽  
Inflammatory Diseases ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Pathway Activation ◽  
Functional Consequences ◽  
International Summit ◽  
The Individual

Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as ‘friend’ or ‘foe’, within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

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

2020 ◽  
Vol 11 ◽  
Author(s):  
Lindsey E. Fox ◽  
Marissa C. Locke ◽  
Deborah J. Lenschow
Keyword(s):  
Viral Infections ◽  
Biological Activities ◽  
Type I Interferons ◽  
Type I ◽  
Disease States ◽  
Type I Ifns ◽  
Wide Range ◽  
Individual Type ◽  
Effector Cytokines ◽  
The Individual

Type I interferons (IFNs) are critical effector cytokines of the immune system and were originally known for their important role in protecting against viral infections; however, they have more recently been shown to play protective or detrimental roles in many disease states. Type I IFNs consist of IFNα, IFNβ, IFNϵ, IFNκ, IFNω, and a few others, and they all signal through a shared receptor to exert a wide range of biological activities, including antiviral, antiproliferative, proapoptotic, and immunomodulatory effects. Though the individual type I IFN subtypes possess overlapping functions, there is growing appreciation that they also have unique properties. In this review, we summarize some of the mechanisms underlying differential expression of and signaling by type I IFNs, and we discuss examples of differential functions of IFNα and IFNβ in models of infectious disease, cancer, and autoimmunity.

Type I interferons produced by dendritic cells promote their phenotypic and functional activation

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3263-3271 ◽  
Author(s):  
Maria Montoya ◽  
Giovanna Schiavoni ◽  
Fabrizio Mattei ◽  
Ion Gresser ◽  
Filippo Belardelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

Abstract Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-α and IFN-β, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti–IFN-α/β antibody to purified splenic DCs in vitro partially blocked the “spontaneous” activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-γ, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

scholarly journals Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

2011 ◽  
Vol 79 (5) ◽  
pp. 2112-2119 ◽  
Author(s):  
Anne-Danielle C. Chessler ◽  
Kacey L. Caradonna ◽  
Akram Da'dara ◽  
Barbara A. Burleigh
Keyword(s):  
Trypanosoma Cruzi ◽  
Parasite Burden ◽  
Host Susceptibility ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Content Type ◽  
Type I Ifns ◽  
Ifn Γ ◽  
The Impact

ABSTRACTTrypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-α/β) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimentalT. cruziinfection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR−/−) 129sv/ev mice were infected with two differentT. cruzistrains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection againstT. cruzi. In contrast, under conditions of lethalT. cruzichallenge, WT mice succumbed to infection whereas IFNAR−/−mice were ultimately able to control parasite growth and survive.T. cruziclearance in and survival of IFNAR−/−mice were accompanied by higher levels of IFN-γ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-γ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-γ and other cytokines/chemokines remains to be fully determined in the context ofT. cruziinfection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-γ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

scholarly journals Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I Interferons

2006 ◽  
Vol 80 (9) ◽  
pp. 4538-4545 ◽  
Author(s):  
Carolina B. López ◽  
Jacob S. Yount ◽  
Tamar Hermesh ◽  
Thomas M. Moran
Keyword(s):  
T Cells ◽  
Virus Infection ◽  
Adaptive Immunity ◽  
Sendai Virus ◽  
Cytotoxic T Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

ABSTRACT Adaptive immunity in response to virus infection involves the generation of Th1 cells, cytotoxic T cells, and antibodies. This type of immune response is crucial for the clearance of virus infection and for long-term protection against reinfection. Type I interferons (IFNs), the primary innate cytokines that control virus growth and spreading, can influence various aspects of adaptive immunity. The development of antiviral immunity depends on many viral and cellular factors, and the extent to which type I IFNs contribute to the generation of adaptive immunity in response to a viral infection is controversial. Using two strains (Cantell and 52) of the murine respiratory Sendai virus (SeV) with differential abilities to induce type I IFN production from infected cells, together with type I IFN receptor-deficient mice, we examined the role of type I IFNs in the generation of adaptive immunity. Our results show that type I IFNs facilitate virus clearance and enhance the migration and maturation of dendritic cells after SeV infection in vivo; however, soon after infection, mice clear the virus from their lungs and efficiently generate cytotoxic T cells independently of type I IFN signaling. Furthermore, animals that are unresponsive to type I IFN develop long-term anti-SeV immunity, including CD8+ T cells and antibodies. Significantly, this memory response is able to protect mice against challenge with a lethal dose of virus. In conclusion, our results show that primary and secondary anti-SeV adaptive immunities are developed normally in the absence of type I IFN responsiveness.

scholarly journals Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Daisy X Ji ◽  
Kristen C Witt ◽  
Dmitri I Kotov ◽  
Shally R Margolis ◽  
Alexander Louie ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Bacterial Infections ◽  
Viral Infections ◽  
Negative Regulator ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Viral Immunity ◽  
Type I Ifns ◽  
Important Negative Regulator

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140-/- mice and find they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis. Susceptibility of Sp140-/- mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar-/-). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections.

scholarly journals Twist mediates suppression of inflammation by type I IFNs and Axl

2006 ◽  
Vol 203 (8) ◽  
pp. 1891-1901 ◽  
Author(s):  
M. Nusrat Sharif ◽  
Dražen Šošić ◽  
Carla V. Rothlin ◽  
Erin Kelly ◽  
Greg Lemke ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Protein S ◽  
Type I Interferons ◽  
Type I ◽  
Transcriptional Repressors ◽  
Inflammatory Cytokine Production ◽  
Type I Ifns ◽  
Twist Expression ◽  
Autoimmune And Inflammatory Diseases ◽  
Axl Receptor Tyrosine Kinase

Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFα production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFα production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFα production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-κB–dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFα production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production.

scholarly journals AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Edward T Schmid ◽  
Iris K Pang ◽  
Eugenio A Carrera Silva ◽  
Lidia Bosurgi ◽  
Jonathan J Miner ◽  
...  
Keyword(s):  
T Cell ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Influenza A ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Enhanced Production ◽  
Cell Immunity

The receptor tyrosine kinase (RTK) AXL is induced in response to type I interferons (IFNs) and limits their production through a negative feedback loop. Enhanced production of type I IFNs in Axl-/- dendritic cells (DCs) in vitro have led to speculation that inhibition of AXL would promote antiviral responses. Notwithstanding, type I IFNs also exert potent immunosuppressive functions. Here we demonstrate that ablation of AXL enhances the susceptibility to infection by influenza A virus and West Nile virus. The increased type I IFN response in Axl-/- mice was associated with diminished DC maturation, reduced production of IL-1β, and defective antiviral T cell immunity. Blockade of type I IFN receptor or administration of IL-1β to Axl-/- mice restored the antiviral adaptive response and control of infection. Our results demonstrate that AXL is essential for limiting the immunosuppressive effects of type I IFNs and enabling the induction of protective antiviral adaptive immunity.

scholarly journals The Yin and Yang of Type I IFNs in Cancer Promotion and Immune Activation

Biology ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 856
Author(s):  
Martina Musella ◽  
Claudia Galassi ◽  
Nicoletta Manduca ◽  
Antonella Sistigu
Keyword(s):  
Deep Understanding ◽  
Type I Interferons ◽  
Host Immune System ◽  
Type I ◽  
Type I Ifn ◽  
Dual Nature ◽  
Adaptive Resistance ◽  
Type I Ifns ◽  
Yin And Yang

Type I Interferons (IFNs) are key regulators of natural and therapy-induced host defense against viral infection and cancer. Several years of remarkable progress in the field of oncoimmunology have revealed the dual nature of these cytokines. Hence, Type I IFNs may trigger anti-tumoral responses, while leading immune dysfunction and disease progression. This dichotomy relies on the duration and intensity of the transduced signaling, the nature of the unleashed IFN stimulated genes, and the subset of responding cells. Here, we discuss the role of Type I IFNs in the evolving relationship between the host immune system and cancer, as we offer a view of the therapeutic strategies that exploit and require an intact Type I IFN signaling, and the role of these cytokines in inducing adaptive resistance. A deep understanding of the complex, yet highly regulated, network of Type I IFN triggered molecular pathways will help find a timely and immune“logical” way to exploit these cytokines for anticancer therapy.

scholarly journals Neutralizing autoantibodies to type I IFNs in >10% of patients with severe COVID-19 pneumonia hospitalized in Madrid, Spain

2021 ◽  
Author(s):  
Jesús Troya García ◽  
Paul Bastard ◽  
Laura Planas-Serra ◽  
Pablo Ryan ◽  
Montse Ruíz ◽  
...  
Keyword(s):  
Severe Pneumonia ◽  
University Hospital ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Protein Levels ◽  
Reactive Protein ◽  
Risk Of Death ◽  
Type I Ifns ◽  
Increased Risk

Abstract Background: In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I IFNs but rarely IFN-beta.Objectives: We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes.Methods: We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain. Results: The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (p=5.10e-03) and lower lymphocyte counts (p=1.80e-02). Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%).Conclusion: Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.

scholarly journals Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Haruna Okude ◽  
Daisuke Ori ◽  
Taro Kawai
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Inflammatory Diseases ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Sensor Molecules

Recognition of pathogen-derived nucleic acids by pattern-recognition receptors (PRRs) is essential for eliciting antiviral immune responses by inducing the production of type I interferons (IFNs) and proinflammatory cytokines. Such responses are a prerequisite for mounting innate and pathogen-specific adaptive immune responses. However, host cells also use nucleic acids as carriers of genetic information, and the aberrant recognition of self-nucleic acids by PRRs is associated with the onset of autoimmune or autoinflammatory diseases. In this review, we describe the mechanisms of nucleic acid sensing by PRRs, including Toll-like receptors, RIG-I-like receptors, and DNA sensor molecules, and their signaling pathways as well as the disorders caused by uncontrolled or unnecessary activation of these PRRs.

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