Limits...
Role of type I interferons in inflammasome activation, cell death, and disease during microbial infection.

Malireddi RK, Kanneganti TD - Front Cell Infect Microbiol (2013)

Bottom Line: Interferons (IFNs) were discovered over a half-century ago as antiviral factors.Deregulated type I IFN production results in a damaging cascade of cell death, inflammation, and immunological host responses that can lead to tissue injury and disease progression.Understanding the specific mechanisms driving type I IFN-mediated cell death and disease could aid in the development of targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, St. Jude Children's Research Hospital Memphis, TN, USA.

ABSTRACT
Interferons (IFNs) were discovered over a half-century ago as antiviral factors. The role of type I IFNs has been studied in the pathogenesis of both acute and chronic microbial infections. Deregulated type I IFN production results in a damaging cascade of cell death, inflammation, and immunological host responses that can lead to tissue injury and disease progression. Here, we summarize the role of type I IFNs in the regulation of cell death and disease during different microbial infections, ranging from viruses and bacteria to fungal pathogens. Understanding the specific mechanisms driving type I IFN-mediated cell death and disease could aid in the development of targeted therapies.

Show MeSH

Related in: MedlinePlus

Mechanisms involved in type I IFN production and its receptor signaling. Several different stimuli including pathogen derived LPS, glycoproteins, RNA and DNA can induce type I IFNs (IFNα and IFNβ) via upstream pattern recognition receptors. TLRs sense the endosomally located PAMPs (pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns) and recruit TRIF (TRL3 and TLR4) or Myd88 (TLR4, 7, 8, and 9), which further transfer the signals downstream to IRF3 and IRF7. RLRs, NLRs, DAI, STING, and related receptors sense nucleic acids in the cytoplasm. The RNA sensors, RIG-I, MDA-5, and LGP2, and DNA sensor STING use the adapter protein MAVS (mitochondrial antiviral signaling protein) to transfer signals to IRFs for type I IFN transcription. RIG-I and MDA-5 also sense ligands generated by RNA polymerase III from cytoplasmic DNA PAMPs. All these pathways utilize the common downstream kinases, TBK1/IKKε for activating Interferon transcription factors. Type I IFNs bind to IFNAR receptor and activate a robust transcriptional pathway through a JAK-STAT signaling pathway. The transcriptional complexes activated by type I IFN signaling bind to specific ISRE/GAS sequences and lead to the expression of several genes important for cell death, cell proliferation and immune responses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824101&req=5

Figure 1: Mechanisms involved in type I IFN production and its receptor signaling. Several different stimuli including pathogen derived LPS, glycoproteins, RNA and DNA can induce type I IFNs (IFNα and IFNβ) via upstream pattern recognition receptors. TLRs sense the endosomally located PAMPs (pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns) and recruit TRIF (TRL3 and TLR4) or Myd88 (TLR4, 7, 8, and 9), which further transfer the signals downstream to IRF3 and IRF7. RLRs, NLRs, DAI, STING, and related receptors sense nucleic acids in the cytoplasm. The RNA sensors, RIG-I, MDA-5, and LGP2, and DNA sensor STING use the adapter protein MAVS (mitochondrial antiviral signaling protein) to transfer signals to IRFs for type I IFN transcription. RIG-I and MDA-5 also sense ligands generated by RNA polymerase III from cytoplasmic DNA PAMPs. All these pathways utilize the common downstream kinases, TBK1/IKKε for activating Interferon transcription factors. Type I IFNs bind to IFNAR receptor and activate a robust transcriptional pathway through a JAK-STAT signaling pathway. The transcriptional complexes activated by type I IFN signaling bind to specific ISRE/GAS sequences and lead to the expression of several genes important for cell death, cell proliferation and immune responses.

Mentions: Interferons (IFNs) are broadly classified into three groups, which are denoted as type I, II, and III based on the specific receptor utilization for their signal transduction. The type I IFN family comprises subtypes of IFNα (13 subtypes), IFNβ, IFNω, and IFNε (Pestka et al., 2004; Hertzog and Williams, 2013). All of the type I IFNs bind to a common heterodimeric receptor, called the IFNα/β receptor (IFNAR), composed of two chains, IFNAR1 and IFNAR2, that are associated with the tyrosine kinases Tyk2 and Jak1. Activated Tyk2 and Jak1 recruit and phosphorylate several signal transducer and activator of transcription (STAT) family members (Figure 1) (Pestka et al., 2004; Platanias, 2005). Activated STAT1 forms a dimer with STAT2, leading to the recruitment of IRF9 and subsequent formation of a heterotrimeric complex called IFN-stimulated gene factor 3 (ISGF3) (Figure 1). This complex translocates to the nucleus, where it binds upstream IFN-stimulated response elements (ISRE) and activates the transcription of type I IFN-inducible genes (Pestka et al., 2004; Platanias, 2005). Type I IFNs are classically known for their antiviral immune responses; however, several studies have demonstrated that a wide range of non-viral pathogens can also induce their expression. However, the specific mechanisms and physiological consequences of IFN responses to such pathogens are poorly understood. Various studies have attributed contrasting roles and differential outcomes to type I IFNs in immune responses to diverse microbial pathogens. The ability of IFNs to regulate cell death has been known for a long time and recent studies have started to reveal the specific mechanisms involved.


Role of type I interferons in inflammasome activation, cell death, and disease during microbial infection.

Malireddi RK, Kanneganti TD - Front Cell Infect Microbiol (2013)

Mechanisms involved in type I IFN production and its receptor signaling. Several different stimuli including pathogen derived LPS, glycoproteins, RNA and DNA can induce type I IFNs (IFNα and IFNβ) via upstream pattern recognition receptors. TLRs sense the endosomally located PAMPs (pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns) and recruit TRIF (TRL3 and TLR4) or Myd88 (TLR4, 7, 8, and 9), which further transfer the signals downstream to IRF3 and IRF7. RLRs, NLRs, DAI, STING, and related receptors sense nucleic acids in the cytoplasm. The RNA sensors, RIG-I, MDA-5, and LGP2, and DNA sensor STING use the adapter protein MAVS (mitochondrial antiviral signaling protein) to transfer signals to IRFs for type I IFN transcription. RIG-I and MDA-5 also sense ligands generated by RNA polymerase III from cytoplasmic DNA PAMPs. All these pathways utilize the common downstream kinases, TBK1/IKKε for activating Interferon transcription factors. Type I IFNs bind to IFNAR receptor and activate a robust transcriptional pathway through a JAK-STAT signaling pathway. The transcriptional complexes activated by type I IFN signaling bind to specific ISRE/GAS sequences and lead to the expression of several genes important for cell death, cell proliferation and immune responses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824101&req=5

Figure 1: Mechanisms involved in type I IFN production and its receptor signaling. Several different stimuli including pathogen derived LPS, glycoproteins, RNA and DNA can induce type I IFNs (IFNα and IFNβ) via upstream pattern recognition receptors. TLRs sense the endosomally located PAMPs (pathogen associated molecular patterns) and DAMPs (damage associated molecular patterns) and recruit TRIF (TRL3 and TLR4) or Myd88 (TLR4, 7, 8, and 9), which further transfer the signals downstream to IRF3 and IRF7. RLRs, NLRs, DAI, STING, and related receptors sense nucleic acids in the cytoplasm. The RNA sensors, RIG-I, MDA-5, and LGP2, and DNA sensor STING use the adapter protein MAVS (mitochondrial antiviral signaling protein) to transfer signals to IRFs for type I IFN transcription. RIG-I and MDA-5 also sense ligands generated by RNA polymerase III from cytoplasmic DNA PAMPs. All these pathways utilize the common downstream kinases, TBK1/IKKε for activating Interferon transcription factors. Type I IFNs bind to IFNAR receptor and activate a robust transcriptional pathway through a JAK-STAT signaling pathway. The transcriptional complexes activated by type I IFN signaling bind to specific ISRE/GAS sequences and lead to the expression of several genes important for cell death, cell proliferation and immune responses.
Mentions: Interferons (IFNs) are broadly classified into three groups, which are denoted as type I, II, and III based on the specific receptor utilization for their signal transduction. The type I IFN family comprises subtypes of IFNα (13 subtypes), IFNβ, IFNω, and IFNε (Pestka et al., 2004; Hertzog and Williams, 2013). All of the type I IFNs bind to a common heterodimeric receptor, called the IFNα/β receptor (IFNAR), composed of two chains, IFNAR1 and IFNAR2, that are associated with the tyrosine kinases Tyk2 and Jak1. Activated Tyk2 and Jak1 recruit and phosphorylate several signal transducer and activator of transcription (STAT) family members (Figure 1) (Pestka et al., 2004; Platanias, 2005). Activated STAT1 forms a dimer with STAT2, leading to the recruitment of IRF9 and subsequent formation of a heterotrimeric complex called IFN-stimulated gene factor 3 (ISGF3) (Figure 1). This complex translocates to the nucleus, where it binds upstream IFN-stimulated response elements (ISRE) and activates the transcription of type I IFN-inducible genes (Pestka et al., 2004; Platanias, 2005). Type I IFNs are classically known for their antiviral immune responses; however, several studies have demonstrated that a wide range of non-viral pathogens can also induce their expression. However, the specific mechanisms and physiological consequences of IFN responses to such pathogens are poorly understood. Various studies have attributed contrasting roles and differential outcomes to type I IFNs in immune responses to diverse microbial pathogens. The ability of IFNs to regulate cell death has been known for a long time and recent studies have started to reveal the specific mechanisms involved.

Bottom Line: Interferons (IFNs) were discovered over a half-century ago as antiviral factors.Deregulated type I IFN production results in a damaging cascade of cell death, inflammation, and immunological host responses that can lead to tissue injury and disease progression.Understanding the specific mechanisms driving type I IFN-mediated cell death and disease could aid in the development of targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, St. Jude Children's Research Hospital Memphis, TN, USA.

ABSTRACT
Interferons (IFNs) were discovered over a half-century ago as antiviral factors. The role of type I IFNs has been studied in the pathogenesis of both acute and chronic microbial infections. Deregulated type I IFN production results in a damaging cascade of cell death, inflammation, and immunological host responses that can lead to tissue injury and disease progression. Here, we summarize the role of type I IFNs in the regulation of cell death and disease during different microbial infections, ranging from viruses and bacteria to fungal pathogens. Understanding the specific mechanisms driving type I IFN-mediated cell death and disease could aid in the development of targeted therapies.

Show MeSH
Related in: MedlinePlus