AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

Luo, Jianmin; Alcorn, John F.; Chen, Kong; Fan, Songqing; Pilewski, Joseph M.; Liu, Aizhong; Chen, Wei; Kolls, Jay K.; Wang, Jieru

doi:10.4049/jimmunol.1600714

Cited by 95 publications

(86 citation statements)

References 59 publications

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“…One study stated that AIM2 dampened detrimental inflammation in the lung microenvironment of mouse infected with IAV and that AIM2‐deficient mice had exacerbated immune responses to IAV . The other study reported that AIM2‐deficient mice infected with IAV infection had less lung tissue damage and improved survival . While these findings may seem contradictory, they both suggest that AIM2 can detect host‐DNA released in the context of viral infections.…”

Section: Aim2 Detection Of Dnamentioning

confidence: 99%

“…Downregulation of AIM2 in SK‐N‐SH cells decreased pyroptosis upon infection with EV‐A71 and augmented viral replication . In contrast AIM2 did not control the replication of Influenza A virus (IAV) in murine models . However, mice lacking AIM2 had reduced lung inflammation and injury after (IAV) infection as illustrated by decreased inflammatory cells infiltrate and decreases lung tissue damage .…”

Section: Aim2 In Health and Diseasementioning

confidence: 99%

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The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

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Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity.

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Section: Aim2 Detection Of Dnamentioning

confidence: 99%

Section: Aim2 In Health and Diseasementioning

confidence: 99%

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Lugrin

Martinon

2017

Immunological Reviews

290

205

View full text Add to dashboard Cite

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“…For example, host‐derived DNA molecules are liberated from virus‐infected cells and accumulate in the lungs following infection by the RNA virus IAV. A study has shown that that AIM2‐deficient mice infected with IAV exhibited attenuated lung injury and significantly improved survival compared with wild‐type mice . Another study, however, has reported that AIM2‐deficient mice had increased susceptibility to IAV infection, owing to increased numbers of infiltrating leukocytes and an exaggerated immune response .…”

Section: Aim2 Inflammasomementioning

confidence: 99%

Molecular mechanisms of inflammasome signaling

Mathur

Hayward

Man

2017

Journal of Leukocyte Biology

153

123

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The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1β and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome.

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“…This recognition leads to the activation of signaling pathways and the production and secretion of IFNs of type I (IFNα and IFNβ) and III (IFNλ2 or IL-28A, IFNλ3 or IL-28B, and IFNλ1 or IL-29), and chemokines and cytokines involved in inflammatory processes [50]. IAV RNAs are mainly recognized by the endosomal, membrane-associated PRR Toll-like receptors (TLRs) 3 (double-stranded RNAs, dsRNAs) or 7/8 (ssRNAs), respectively [50,51], by the cytoplasmic PRR retinoic acid-inducible gene I (RIG-I), which detects dsRNA and 5 -triphosphates of the negative ssRNA viral genome [50,52], generated during replication of multiple viruses, by the NOD-like receptor family member NOD-, LRR-and pyrin domain-containing 3 (NLRP3), which recognizes various stimuli (see below) [53] and by the absent in melanoma 2 (AIM2) protein, recognizing not well-characterized influenza stimuli [54]. The result of PRR detection of viral PAMPs is the activation of multiple transcription factors, such as the nuclear factor kappa β (NF-κB), the activator protein 1 (AP-1), and IFN regulatory factors (IRF)-3 and IRF-7, which are responsible for the transcription of IFNs [50,55,56] and pro-inflammatory cytokines [57].…”

Section: Innate Immunity In Iav Infectionsmentioning

confidence: 99%

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

Nogales¹,

DeDiego

2019

Pathogens

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A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness. multiple mechanisms, although there are some differences between strains. For that genome plasticity, IAV take advantage of multiple strategies, such as alternative splicing, frameshift mechanisms, and overlapping open reading frames (ORFs) [7][8][9]. In addition, the coding capability of the viral genome is extended by encoding multifunctional proteins that act at different steps during virus infection. of synthetized vRNP, ensuring that the vRNPs are available for packaging [24]. Moreover, NEP has also other functions during IAV infection, contributing to viral budding and to regulate viral RNA synthesis. NS1 is a multifunctional protein and a key viral factor that counteracts the host antiviral responses. NS1 has been shown to inhibit the production of interferon (IFN), the activity and expression of multiple interferon-induced genes (ISG) and the processing and nuclear transport of host mRNAs causing cellular shut-off [25,26]. Segment 3 of IAV also encodes two proteins, the polymerase component PA and PA-X. PA is translated directly from the PA mRNA, whereas PA-X is translated using a +1 frameshift mechanism from the same open reading frame (ORF) [9]. Synergistically with NS1, PA-X is also able to block the cellular antiviral responses by inhibiting host protein expression. Moreover, the PA-X protein has been shown to modulate host inflammation, immune responses, apoptosis, and virus pathogenesis [25][26][27][28][29][30].

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AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

Cited by 95 publications

References 59 publications

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

Molecular mechanisms of inflammasome signaling

Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

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