AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA
ABSTRACT Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotr...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2017-09-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.00944-17 |
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| author | Yuki Nakaya Jingtao Lilue Spyridon Stavrou Eileen A. Moran Susan R. Ross |
| author_facet | Yuki Nakaya Jingtao Lilue Spyridon Stavrou Eileen A. Moran Susan R. Ross |
| author_sort | Yuki Nakaya |
| collection | DOAJ |
| description | ABSTRACT Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA. IMPORTANCE Autoimmune diseases like Aicardi-Goutières syndrome and lupus erythematosus arise when cells of the immune system become activated and attack host cells and tissues. We found that DNA generated by endogenous retroviruses and retroelements in inbred mice and mouse cells is recognized by several host proteins found in macrophages that are members of the ALR family and that these proteins both suppress and activate the pathways leading to the generation of cytokines and IFNs. We also show that there is great genetic diversity between different inbred mouse strains in the ALR genes, which might contribute to differential susceptibility to autoimmunity. Understanding how immune cells become activated is important to the control of disease. |
| first_indexed | 2024-12-21T09:27:55Z |
| format | Article |
| id | doaj.art-d254c4edf75e434e8607b6b4b3122261 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-21T09:27:55Z |
| publishDate | 2017-09-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-d254c4edf75e434e8607b6b4b31222612022-12-21T19:08:51ZengAmerican Society for MicrobiologymBio2150-75112017-09-018410.1128/mBio.00944-17AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNAYuki Nakaya0Jingtao Lilue1Spyridon Stavrou2Eileen A. Moran3Susan R. Ross4Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USAWellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United KingdomDepartment of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USADepartment of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USADepartment of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USAABSTRACT Cytosolic DNAs derived from retrotransposons serve as pathogen-associated molecular patterns for pattern recognition receptors (PRRs) that stimulate the induction of interferons (IFNs) and other cytokines, leading to autoimmune disease. Cyclic GMP-AMP synthase is one PRR that senses retrotransposon DNA, activating type I IFN responses through the stimulator of IFN genes (STING). Absent in melanoma 2 (AIM2)-like receptors (ALRs) have also been implicated in these pathways. Here we show that the mouse ALR IFI205 senses cytosolic retrotransposon DNA independently of cyclic GMP-AMP production. AIM2 antagonizes IFI205-mediated IFN induction activity by sequestering it from STING. We also found that the complement of genes located in the ALR locus in C57BL/6 and AIM2 knockout mice are different and unique, which has implications for interpretation of the sensing of pathogens in different mouse strains. Our data suggest that members of the ALR family are critical to the host IFN response to endogenous DNA. IMPORTANCE Autoimmune diseases like Aicardi-Goutières syndrome and lupus erythematosus arise when cells of the immune system become activated and attack host cells and tissues. We found that DNA generated by endogenous retroviruses and retroelements in inbred mice and mouse cells is recognized by several host proteins found in macrophages that are members of the ALR family and that these proteins both suppress and activate the pathways leading to the generation of cytokines and IFNs. We also show that there is great genetic diversity between different inbred mouse strains in the ALR genes, which might contribute to differential susceptibility to autoimmunity. Understanding how immune cells become activated is important to the control of disease.https://journals.asm.org/doi/10.1128/mBio.00944-17ALRAim2Trex1endogenous retrovirusretrotransposonself DNA |
| spellingShingle | Yuki Nakaya Jingtao Lilue Spyridon Stavrou Eileen A. Moran Susan R. Ross AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA mBio ALR Aim2 Trex1 endogenous retrovirus retrotransposon self DNA |
| title | AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA |
| title_full | AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA |
| title_fullStr | AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA |
| title_full_unstemmed | AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA |
| title_short | AIM2-Like Receptors Positively and Negatively Regulate the Interferon Response Induced by Cytosolic DNA |
| title_sort | aim2 like receptors positively and negatively regulate the interferon response induced by cytosolic dna |
| topic | ALR Aim2 Trex1 endogenous retrovirus retrotransposon self DNA |
| url | https://journals.asm.org/doi/10.1128/mBio.00944-17 |
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