The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

Gaidt, Moritz M.; Ebert, Thomas S.; Chauhan, Dhruv; Ramshorn, Katharina; Pinci, Francesca; Zuber, Sarah P; O’Duill, Fionan; Schmid-Burgk, Jonathan L.; Hoß, Florian; Buhmann, Raymund; Wittmann, Georg; Latz, Eicke; Subklewe, Marion; Hornung, Veit

doi:10.1016/j.cell.2017.09.039

Cited by 470 publications

(489 citation statements)

References 54 publications

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“…Infection of IFNγ‐primed human THP1 cells with L. monocytogenes strain 10403S results in enhanced NLRP3 activation assisted by the IFNγ‐inducible GBP5 (Shenoy et al, ). Altogether, these studies are consistent with the recently identified AIM2‐independent, NLRP3‐dependent detection of cytosolic DNA in human, but not mouse, myeloid cells (Gaidt et al, ). This new DNA‐sensing pathway in human cells also requires lysosomal damage (Gaidt et al, ).…”

Section: Monocytogenes Benefits From Inflammasome Activationsupporting

confidence: 90%

“…Altogether, these studies are consistent with the recently identified AIM2‐independent, NLRP3‐dependent detection of cytosolic DNA in human, but not mouse, myeloid cells (Gaidt et al, ). This new DNA‐sensing pathway in human cells also requires lysosomal damage (Gaidt et al, ). Therefore, L. monocytogenes , plausibly via both LLO and release of DNA in the cytosol, activates the human NLRP3 inflammasome and the murine AIM2 inflammasome (Figure d).…”

Section: Monocytogenes Benefits From Inflammasome Activationsupporting

confidence: 90%

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Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Sanchez‐Garrido

Slater

Clements

et al. 2020

Cellular Microbiology

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Enteric pathogen–host interactions occur at multiple interfaces, including the intestinal epithelium and deeper organs of the immune system. Microbial ligands and activities are detected by host sensors that elicit a range of immune responses. Membrane‐bound toll‐like receptors and cytosolic inflammasome pathways are key signal transducers that trigger the production of pro‐inflammatory molecules, such as cytokines and chemokines, and regulate cell death in response to infection. In recent years, the inflammasomes have emerged as a key frontier in the tussle between bacterial pathogens and the host. Inflammasomes are complexes that activate caspase‐1 and are regulated by related caspases, such as caspase‐11, ‐4, ‐5 and ‐8. Importantly, enteric bacterial pathogens can actively engage or evade inflammasome signalling systems. Extracellular, vacuolar and cytosolic bacteria have developed divergent strategies to subvert inflammasomes. While some pathogens take advantage of inflammasome activation (e.g. Listeria monocytogenes, Helicobacter pylori), others (e.g. E. coli, Salmonella, Shigella, Yersinia sp.) deploy a range of virulence factors, mainly type 3 secretion system effectors, that subvert or inhibit inflammasomes. In this review we focus on inflammasome pathways and their immune functions, and discuss how enteric bacterial pathogens interact with them. These studies have not only shed light on inflammasome‐mediated immunity, but also the exciting area of mammalian cytosolic immune surveillance.

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Section: Monocytogenes Benefits From Inflammasome Activationsupporting

confidence: 90%

Section: Monocytogenes Benefits From Inflammasome Activationsupporting

confidence: 90%

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Sanchez‐Garrido

Slater

Clements

et al. 2020

Cellular Microbiology

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“…It is also important to highlight that most of the available data on the role of inflammasomes in epithelial cell immunity has been obtained using either human cell lines, or primary epithelial cells from mouse. Key differences between human and murine inflammasomes have already been described (for instance NLRC4 is not activated by the same components of bacterial flagellum in mouse and humans and DNA inflammasome activation in human monocytes depends on NLRP3 instead of AIM2). Therefore, more studies are needed in human lung epithelial cells to confirm the findings mentioned in this review.…”

Section: The Inflammasome: a Well‐regulated Immune Platform Also Presmentioning

confidence: 99%

The inflammasomes, immune guardians at defence barriers

Palazón-Riquelme

López-Castejón

2018

Immunology

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SummaryAs a result of its strategic location, the epithelium is constantly exposed to a wide variety of pathogen and danger signals. Traditionally, the epithelium has been perceived as a defensive but passive barrier; however, it has now become evident that the epithelium senses and actively responds to these signals in order to maintain barrier homeostasis and contributes to the inflammatory response. One way it does this is by producing pro‐inflammatory cytokines including interleukin‐1β (IL‐1β) and IL‐18. These two cytokines are synthesized as inactive precursors, the maturation of which is mediated by pro‐inflammatory caspases after the activation and assembly of macromolecular complexes called inflammasomes. Epithelial cells express a large panel of inflammasome components, and although the molecular mechanisms underlying the activation of these complexes in haematopoietic cells are well understood, how epithelial cells react to danger signals to activate the inflammasome remains unclear. We review and discuss how different inflammasomes contribute to barrier homeostasis and inflammation at several barrier sites, their mechanisms and how their aberrant regulation contributes to disease at the different epithelia.

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“…The AIM2-like receptors (ALR), of which there are 4 in humans and 13 in mice, have in common a DNA-binding HIN domain and a Pyrin signaling domain. (63), The biologic role for all of these DNA sensors in vivo , aside from Cyclic GMP-AMP synthase (cGAS), has been questioned (64) and a recent study suggests that cGAS-STING, rather than AIM2 is responsible for inflammasome activation in myeloid cells (65). We will therefore focus on the sensor, cGAS.…”

Section: Nucleic Acids Stimulate Pattern Recognition Receptors To Indmentioning

confidence: 99%

Review: Cell Death, Nucleic Acids, and Immunity

Elkon

2018

Arthritis & Rheumatology

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Cells of the innate immune system are rigged with sensors that detect nucleic acids derived from microbes, especially viruses. It has become clear that these same sensors that respond to nucleic acids derived from damaged cells or defective intracellular processing are implicated in triggering diseases such as lupus and arthritis. The ways in which cells die and the concomitant presence of proteins and peptides that allow nucleic acids to re-enter cells profoundly influence innate immune responses. In this review, we briefly discusses different types of programmed necrosis, such as pyroptosis, necroptosis, and NETosis, and explains how nucleic acids can engage intracellular receptors and stimulate inflammation. Host protective mechanisms that include compartmentalization of receptors and nucleases as well as the consequences of nuclease deficiencies are explored. In addition, proximal and distal targets in the nucleic acid stimulation of inflammation are discussed in terms of their potential amenability to therapy for the attenuation of innate immune activation and disease pathogenesis.

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The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell Death Program Upstream of NLRP3

Cited by 470 publications

References 54 publications

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

Vying for the control of inflammasomes: The cytosolic frontier of enteric bacterial pathogen–host interactions

The inflammasomes, immune guardians at defence barriers

Review: Cell Death, Nucleic Acids, and Immunity

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