Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Mar 10:8:259.
doi: 10.3389/fimmu.2017.00259. eCollection 2017.

Type I Interferons as Regulators of Lung Inflammation

Spyridon Makris  1 , Michelle Paulsen  1 , Cecilia Johansson  1
Affiliations
Review

Type I Interferons as Regulators of Lung Inflammation

Spyridon Makris et al. Front Immunol. .

Abstract

Immune responses to lung infections must be tightly regulated in order to permit pathogen eradication while maintaining organ function. Exuberant or dysregulated inflammation can impair gas exchange and underlies many instances of lung disease. An important driver of inflammation in the lung is the interferon (IFN) response. Type I IFNs are antiviral cytokines that induce a large range of proteins that impair viral replication in infected cells. This cell-intrinsic action plays a crucial role in protecting the lungs from spread of respiratory viruses. However, type I IFNs have also recently been found to be central to the initiation of lung inflammatory responses, by inducing recruitment and activation of immune cells. This helps control virus burden but can cause detrimental immunopathology and contribute to disease severity. Furthermore, there is now increasing evidence that type I IFNs are not only induced after viral infections but also after infection with bacteria and fungi. The pro-inflammatory function of type I IFNs in the lung opens up the possibility of immune modulation directed against this antiviral cytokine family. In this review, the initiation and signaling of type I IFNs as well as their role in driving and maintaining lung inflammation will be discussed.

Keywords: infection; inflammation; lung; pattern recognition receptors; type I interferons.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Pattern recognition receptor signaling that leads to the induction of type I interferons (IFNs). The endosomally expressed TLR-3, -7, -8, and -9, cell surface expressed TLR4, the RLRs [retinoic acid-inducible gene I (RIG)-I and MDA-5], and cGAMP synthase (cGAS) can couple pathogen detection to type I IFN induction. TLR3 and TLR4 signal via TRIF, which occurs through inhibitor of kappa-B (IκB) kinases (IKKs), tumor necrosis factor (TNF) receptor-associated factor (TRAF) family associated NF-κB activator (TANK)-binding kinase-1 (TBK1), and IKK-ɛ. This causes the activation of IRF3, which in turn induces the expression of type I IFNs. The activation of TLR3 can also induce the production of inflammatory mediators via TRIF by activating a complex formed by TRAF-6, TNF receptor type I DEATH domain-associated protein (TRADD), Pellino-1, and the receptor-interacting kinase (RIP)-1. This causes the activation of NF-κB pathway, which is mediated by the IKK complex and transforming growth factor beta activated kinase (TAK)-1. TLR7, 8, and 9 use MyD88 for downstream signaling and can activate IRF and NF-κB pathways. RIG-I and MDA5 signal through the adaptor molecule mitochondrial antiviral signaling protein (MAVS). cGAS signals via the adaptor protein stimulator of interferon genes (STING). MAVS and STING further recruit signaling molecules (involving the IKK complex, TBK1, and several TRAF proteins) and lead to the activation of NF-κB and IRF3, resulting in gene expression of various antiviral cytokines including type I IFNs (–13).
Figure 2
Figure 2
Type I interferon (IFN) signaling. Type I IFNs bind to the heterodimeric transmembrane IFN-α/β receptor (IFNAR), which is composed of the two subunits: IFNAR1 and IFNAR2. The c-termini of IFNAR1 and IFNAR2 are associated with the tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1), respectively, and activation of the receptor transduces the phosphorylation of JAK1 and TYK2 by tyrosine phosphorylation. This initiates a signaling cascade composed of proteins of the signal transducer and activator of transcription (STAT) family. The STAT1 and STAT2 proteins are activated upon JAK1 phosphorylation, dimerize and together with IRF9, form the ISG factor 3 (ISGF3) complex. This complex translocates to the nucleus and binds to IFN-stimulated response elements (ISREs) in interferon-stimulated genes (ISGs) promoters to initiate gene transcription. Signaling through IFNAR can also occur independent of IRF9 recruitment through STAT1 homodimers that can bind to IFN-γ-activated sites (GAS) in ISG promoters. Both pathways initiate transcription that promotes the induction of a range of pro-inflammatory mediators and enhance the antiviral state. The JAK–TYK signaling pathway can also promote signaling pathways independent of STAT signaling. One such pathway includes MAPKs, which are important for signals regulating important cellular functions such as gene transcription, post-transcription, apoptosis, and cell-cycle progression. Specifically, the p38 signaling cascade after IFN-stimulation drives transcription of genes that are important for inducing the antiviral effects of type I IFNs and are regulated by ISREs and GAS. Further to MAPK, the type I IFN receptor signaling can also activate the phosphoinositide 3-kinase (PI3K) signaling pathway. The phosphorylation of PI3K causes the activation of the RAC-α serine/threonine-protein kinase (AKT1)/cAMP responsive-element-binding protein that can bind smad binding elements (SBE). This signaling pathway is believed to be important for transcription of genes controlling cellular survival and inflammatory (, –40).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Kopf M, Schneider C, Nobs SP. The development and function of lung-resident macrophages and dendritic cells. Nat Immunol (2014) 16:36–44.10.1038/ni.3052 - DOI - PubMed
    1. Durbin RK, Kotenko SV, Durbin JE. Interferon induction and function at the mucosal surface. Immunol Rev (2013) 255:25–39.10.1111/imr.12101 - DOI - PMC - PubMed
    1. González-Navajas JM, Lee J, David M, Raz E. Immunomodulatory functions of type I interferons. Nat Rev Immunol (2012) 12:125–35.10.1038/nri3133 - DOI - PMC - PubMed
    1. Swiecki M, Colonna M. Type I interferons: diversity of sources, production pathways and effects on immune responses. Curr Opin Virol (2011) 1:463–75.10.1016/j.coviro.2011.10.026 - DOI - PMC - PubMed
    1. Wack A, Terczyńska-Dyla E, Hartmann R. Guarding the frontiers: the biology of type III interferons. Nat Immunol (2015) 16:802–9.10.1038/ni.3212 - DOI - PMC - PubMed