Rhinovirus-induced IFNβ expression is NFκB-dependent and regulated by the macrophage microenvironment

Menzel, Mandy; Kosinski, Joakim; Uller, Lena; Akbarshahi, Hamid

doi:10.1038/s41598-019-50034-1

Cited by 7 publications

(2 citation statements)

References 39 publications

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“…Our study supported this view: we found that IFNβ expression was consistently higher in NFκB1 −/− mice and, unlike in wild-type mice, was not reduced at exacerbation. This is in line with a previous study in which blocking of IκB kinase enhanced IFNβ expression in macrophages primed with Th2 cytokines [38]. We further demonstrated that enhanced expression of IFNβ in NFκB1-deficient mice at exacerbation was associated with an upregulation of antiviral signaling mediated by higher gene levels of IRF3 and IRF7.…”

Section: Discussion/conclusionsupporting

confidence: 93%

NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

et al. 2021

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Asthma exacerbations are commonly triggered by rhinovirus infections. Viruses can activate the NFκB pathway resulting in airway inflammation and increased Th2 cytokine expression. NFκB signaling is also involved in early activation of IFNβ, which is a central mediator of antiviral responses to rhinovirus infection. Using a mouse model, this study tests our hypothesis that NFκB signaling is involved in impaired IFNβ production at viral-induced asthma exacerbations. C57BL/6 wild-type and NFκB1<sup>−/−</sup> mice were challenged with house dust mite for 3 weeks and were subsequently stimulated with the rhinoviral mimic poly(I:C). General lung inflammatory parameters and levels of the Th2 upstream cytokine IL-33 were measured after allergen challenge. At exacerbation, production of IFNβ and antiviral proteins as well as gene expression of pattern recognition receptors and IRF3/IRF7 was assessed. In the asthma exacerbation mouse model, lack of NFκB1 resulted in lower levels of IL-33 after allergen challenge alone and was associated with reduced eosinophilia. At exacerbation, mice deficient in NFκB1 exhibited enhanced expression of IFNβ and antiviral proteins. This was accompanied by increased IRF3/IRF7 expression and induction of pattern recognition receptor expression. In a human asthma dataset, a negative correlation between IRF3 and NFκB1 expression was observed. NFκB may impair antiviral responses at exacerbation, possibly by reducing expression of the transcription factors IRF3/IRF7. These findings suggest a therapeutic potential for targeting NFκB pathways at viral infection-induced exacerbations.

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Section: Discussion/conclusionsupporting

confidence: 93%

NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

et al. 2021

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“…Immunomodulatory therapies target AMs that exist in multiple potential sites during a viral infection of the respiratory tract. In the case of rhinovirus infection, AMs can be M1/M2 polarized by GM-CSF/M-CSF or IFN-γ/IL-4 stimulation ( 86 , 87 ). M1/M2 herein can be likewise classified by their functions and origins rather than dichotomy.…”

Section: Prospect Of Ams As Target For the Treatment Of Ahr-related V...mentioning

confidence: 99%

Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection

et al. 2022

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Respiratory syncytial virus (RSV) is a ubiquitous pathogen of viral bronchiolitis and pneumonia in children younger than 2 years of age, which is closely associated with recurrent wheezing and airway hyperresponsiveness (AHR). Alveolar macrophages (AMs) located on the surface of the alveoli cavity are the important innate immune barrier in the respiratory tract. AMs are recognized as recruited airspace macrophages (RecAMs) and resident airspace macrophages (RAMs) based on their origins and roaming traits. AMs are polarized in the case of RSV infection, forming two macrophage phenotypes termed as M1-like and M2-like macrophages. Both M1 macrophages and M2 macrophages are involved in the modulation of inflammatory responses, among which M1 macrophages are capable of pro-inflammatory responses and M2 macrophages are capable of anti-proinflammatory responses and repair damaged tissues in the acute and convalescent phases of RSV infection. Polarized AMs affect disease progression through the alteration of immune cell surface phenotypes as well as participate in the regulation of T lymphocyte differentiation and the type of inflammatory response, which are closely associated with long-term AHR. In recent years, some progress have been made in the regulatory mechanism of AM polarization caused by RSV infection, which participates in acute respiratory inflammatory response and mediating AHR in infants. Here we summarized the role of RSV-infection-mediated AM polarization associated with AHR in infants.

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NF-κB, A Potential Therapeutic Target in Cardiovascular Diseases

Cheng

Cui

Liu

et al. 2022

Cardiovasc Drugs Ther

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Cardiovascular diseases (CVDs) are the leading cause of death globally. Atherosclerosis is the basis of major CVDs -myocardial ischemia, heart failure and stroke. Among numerous functional molecules, the transcription factor nuclear factor κB (NF-κB) has been linked to downstream target genes involved in atherosclerosis. The activation of NF-κB family and its downstream target genes in response to environmental and cellular stress, hypoxia and ischemia initiate different pathological events such as innate and adaptive immunity, and cell survival, differentiation and proliferation. Thus, NF-κB is a potential therapeutic target in the treatment of atherosclerosis and related CVDs. Several biologics and small molecules as well as peptide/proteins have been shown to regulate NF-κB dependent signaling pathways. In this review, we will focus on the function of NF-κB in CVDs and the role of NF-κB inhibitors in the treatment of CVDs. IntroductionCardiovascular diseases (CVDs) are the leading causes of death in the Western hemisphere and rapidly becoming so in the developing world. While the major risk factors leading to CVDs have been well addressed and targeted to prevent and treat CVDs, the precise steps and molecular mechanism leading to atherogenesis and its major manifestations are yet being described. Here we focus on nuclear-factor kappa beta (NF-κB) as an important transcription factors involved in several steps in the development of CVDs. N F-κB familyMany genes contain a nearly palindromic DNA sequence with a consensus of 50-GGGRNWYYCC-30 (N, any base; R, purine; W, adenine or thymine; Y, pyrimidine), which is termed κB [1]. The elements in enhancers or promoters of these genes can be recognized by a class of proteins such as NF-κB that subsequently initiate the transcription of these genes. NF-κB in mammals is a family of ve related proteins: RelAIp65, RelB, c-Rel, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100) (Fig. 1-part I) [2]. These subunits share N-terminal Rel homology domain (RHD) with the v-Rel oncogene and form dimers that can positively or negatively regulate gene expression. RHD is responsible for homo-and heterodimerization as well as for sequence-speci c DNA binding to κB sites. NF-κB family contains two subfamilies: p65, RelB and c-Rel containing a C-terminal transcriptional transactivation domain (TAD) which confers the ability to promote gene expression; p50 and p52 lacking a TAD have a dual role (Fig. 1-part I). Homodimers of p50 and p52 are thought to repress transcription through competing with transcriptionally active dimers to bind to their DNA targets. While they are bound to p65, RelB or c-Rel as part of a heterodimer, p50 and p52 can promote transcription. RelB is unique in that it also contains an N-terminal leucine zipper (LZ) region that needs to work with its TAD to be fully functional. Since RelB has only been veri ed to form dimers with p50 and p52, there are only 12 dimers existing in cells. The C-terminal death domain (DD) in C-terminal half of p10...

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Rhinovirus-induced IFNβ expression is NFκB-dependent and regulated by the macrophage microenvironment

Cited by 7 publications

References 39 publications

NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

NFκB1 Dichotomously Regulates Pro-Inflammatory and Antiviral Responses in Asthma

Alveolar macrophages and airway hyperresponsiveness associated with respiratory syncytial virus infection

NF-κB, A Potential Therapeutic Target in Cardiovascular Diseases

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