Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation

Ma, Chunmei; Yang, Dongxue; Wang, Bingwei; Wu, Chunyan; Wu, Yuqing; Li, Sheng; Li, Xue; Lassen, Kara G.; Dai, Lue; Yang, Shuo

doi:10.1126/sciadv.aaz6717

Cited by 98 publications

(95 citation statements)

References 40 publications

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“…In brief, following a response to DNA damage, cytosolic self-DNA escapes into the cytosol where it is recognized by the cGAS-STING pathway, which then stimulates the production of interferons and inflammatory factors [ 55 ]. The SASPs activated by interferon signaling following the activation of cGAS-STING include CXCL10 and genes that play a critical role in interferon signaling, including IFNβ, ISG15, MX2, and OASL2 [ 56 , 57 , 58 , 59 , 60 ]. In our study, we evaluated the mRNA expression of these genes in oxidative stress conditions in preadipocytes in the absence of cGAS and STING.…”

Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

et al. 2021

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Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling—it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.

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Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

et al. 2021

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“…53 The cross talk between inflammasome and cGAS occurs not only during infections but also during sterile inflammation as well; GSDMD deficiency augments cGAS-dependent type I IFN response and worsens intestinal inflammation in a DSS colitis model. 106 Overall, these studies clearly establish a crosstalk between the inflammasome and type I interferon pathways and its critical role in a broad range of host-pathogen interactions as well as sterile inflammation.…”

Section: Cross Talk B E T Ween the Aim2 Infl Amma Some And Other Dnmentioning

confidence: 84%

AIM2 in health and disease: Inflammasome and beyond

Kumari

Russo

Shivcharan

et al. 2020

Immunological Reviews

121

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Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline‐encoded innate immune receptors detect microbial DNA in various compartments of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor‐dependent type I IFN synthesis followed by JAK/STAT‐dependent interferon‐stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase‐1. Caspase‐1 cleaves and activates the pro‐inflammatory cytokines such as IL‐1β and IL‐18 and a pore‐forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome‐dependent and inflammasome‐independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.

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“…These factors in turn activate the expression of pro-inflammatory cytokines, chemokines, and interferons, potentially driving inflammation. Altogether, this study suggests a protective function of the pyroptosis executioner Gasdermin D in macrophages during inflammation [ 107 ].…”

Section: Macrophages During Intestinal Inflammationmentioning

confidence: 85%

At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine

Ruder

Becker

2020

Cells

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Macrophages are part of the innate immunity and are key players for the maintenance of intestinal homeostasis. They belong to the group of mononuclear phagocytes, which exert bactericidal functions and help to clear apoptotic cells. Moreover, they play essential roles for the maintenance of epithelial integrity and tissue remodeling during wound healing processes and might be implicated in intestinal tumor development. Macrophages are antigen-presenting cells and secrete immune-modulatory factors, like chemokines and cytokines, which are necessary to activate other intestinal immune cells and therefore to shape immune responses in the gut. However, overwhelming activation or increased secretion of pro-inflammatory cytokines might also contribute to the pathogenesis of inflammatory bowel disease. Presently, intestinal macrophages are in the center of intense studies, which might help to develop new therapeutic strategies to counteract the development or treat already existing inflammatory diseases in the gut. In this review, we focus on the origin of intestinal macrophages and, based on current knowledge, discuss their role in the gut during homeostasis and inflammation, as well as during intestinal wound healing and tumor development.

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Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation

Cited by 98 publications

References 40 publications

Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes

AIM2 in health and disease: Inflammasome and beyond

At the Forefront of the Mucosal Barrier: The Role of Macrophages in the Intestine

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