Influenza Virus-Induced Oxidized DNA Activates Inflammasomes

Moriyama, Miyu; Nagai, Minami; Maruzuru, Yuhei; Koshiba, Takumi; Kawaguchi, Yasushi; Ichinohe, Takeshi

doi:10.1016/j.isci.2020.101270

Cited by 38 publications

(33 citation statements)

References 56 publications

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“…AIM2 is a dsDNA sensor that is mainly activated in monocytes and macrophages by cytoplasmic DNA, derived from pathogens or neighboring necrotic cells (Briard et al 2020 ). In addition, there is accumulating evidence for AIM2 to be involved in sustaining mitochondrial function by detecting mitochondrial DNA (mtDNA) in various human diseases, including cancer and diabetes type 2 (Bae et al 2019 ; Qi et al 2020 ), as well as in detecting virus-induced oxidized DNA (Moriyama et al 2020 ). In neurodevelopment, AIM2 was recently shown to be involved in surveillance of DNA damage of neurons (Lammert et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

Wortmann

Arshad

Hakimi

et al. 2020

Mol Med

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Background Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods Aim2−/− mice and wild-type (WT) C57Bl/6 J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro. Young (passage 3–5) and senescent (passage 7–12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results Compared with VSMC from WT mice, VSMC isolated from Aim2−/− mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2−/− mice versus 76.5% (13/17) in WT mice. In contrast to Aim2−/− mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/Acta2, indicating tissue remodeling. Reduced cell proliferation in Aim2−/− mice was indicated by significantly increased p16ink4a/Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2−/− mice. Conclusions Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA formation.

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Section: Discussionmentioning

confidence: 99%

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

Wortmann

Arshad

Hakimi

et al. 2020

Mol Med

View full text Add to dashboard Cite

show abstract

“…AIM2 is a dsDNA sensor that is mainly activated in monocytes and macrophages by cytoplasmic DNA, derived from pathogens or neighboring necrotic cells (Briard et al, 2020). In addition, there is accumulating evidence for AIM2 to be involved in sustaining mitochondrial function by detecting mitochondrial DNA (mtDNA) in various human diseases, including cancer and diabetes type 2 (Bae et al, 2019;Qi et al, 2020), as well as in detecting virus-induced oxidized DNA (Moriyama et al, 2020). In neurodevelopment, AIM2 was recently shown to be involved in surveillance of DNA damage of neurons (Lammert et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

Wortmann

Arshad

Hakimi

et al. 2020

Preprint

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Background: Phenotypic transformation of vascular smooth muscle cells is a key element in vascular remodeling and aortic aneurysm growth. Previously, deletion of several inflammasome components decreased formation of aortic aneurysm (AA) in the Angiotensin II (AngII) -induced mouse model. We hypothesized that the inflammasome sensor Absent in melanoma 2 (Aim2) might affect the phenotype of vascular smooth muscle cells (VSMC), thereby reducing AA formation. Methods : Aim2-/- mice and wild-type (WT) C57Bl/6J mice were used as an animal model. VSMC were isolated from 6 months old mice and grown in vitro . Young (passage 3-5) and senescent (passage 7-12) cells were analyzed in vitro for calcification in mineralization medium by Alizarin Red S staining. Expression of calcification and inflammatory markers were studied by real-time RT-PCR and Western blotting, release of cytokines was determined by ELISA. To induce AA, osmotic mini-pumps loaded with AngII (1500 ng/kg bodyweight/min) were implanted for 28 days in male mice at 6 months of age. Results : Compared with VSMC from WT mice, VSMC isolated from Aim2-/- mice were larger, less viable, and underwent stronger calcification in mineralization medium, along with induction of Bmp4 and repression of Tnfsf11/Rankl gene expression. In addition, Aim2 deficiency was associated with reduced inflammasome gene expression and release of Interleukin-6. Using the mouse model of AngII induced AA, Aim2 deficiency reduced AA incidence to 48.4% (15/31) in Aim2-/- mice versus 76.5% (13/17) in WT mice. In contrast to Aim2-/- mice, AA from WT mice expressed significantly increased levels of alpha-smooth muscle actin/ Acta2 , indicating tissue remodeling. Reduced cell proliferation in Aim2-/- mice was indicated by significantly increased p16ink4a/ Cdkn2a expression in untreated and AngII-infused aortas, and by significantly lower amounts of proliferating (Ki67 positive) VSMC in AngII-infused Aim2-/- mice. Conclusions: Our results suggest a role for Aim2 in regulating VSMC proliferation and transition to an osteoblast-like or osteoclast-like phenotype, thereby modulating the response of VSMC in aortic remodeling and AA Formation.

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“…I will discuss here only its role in recognizing self-DNA during different inflammatory conditions or diseases. The AIM2-mediated inflammasome activation has been observed in the influenza virus infection in macrophages due to the release of mtDNA from the infected macrophages ( 285 ). The AIM2 recognizes mtDNA that forms ASC-dependent inflammasome and releases mature IL-1β.…”

Section: Alrs Recognizing Self-dnamentioning

confidence: 99%

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

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Influenza Virus-Induced Oxidized DNA Activates Inflammasomes

Cited by 38 publications

References 56 publications

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and angiotensin-II induced aortic aneurysms

Deficiency in Aim2 affects viability and calcification of vascular smooth muscle cells from murine aortas and Angiotensin-II induced aortic aneurysms

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

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