Autophagy and Inflammatory Cell Death, Partners of Innate Immunity

Swanson, Michele S.; Molofsky, Ari B.

doi:10.4161/auto.1.3.2067

Cited by 48 publications

(41 citation statements)

References 27 publications

(31 reference statements)

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“…23,24 Although pyroptosis was first recognized in cells infected with intracellular pathogens, [22][23][24] our results show that non-infectious agents like LPS, R837, MSU, SAT or lipopeptides can all induce pyroptosis in human THP-1 cells in the absence of an added ATP stimulus. Pyroptosis can also be induced in primary mouse bone marrow macrophages with LPS, but requires high concentrations of ATP as a second stimulus (Figure 3 …”

Section: Discussionmentioning

confidence: 65%

“…[22][23][24][25] Pyroptosis was initially observed in macrophages infected with the intracellular bacteria S.typhimurium, 26 but was later found to occur in response to infection with a number of other intracellular bacterial and viral pathogens (reviewed in Swanson MS 22 and Fink SL 24 ). An inflammatory form of cell death not caused by pathogenic infection, but similar to pyroptosis, was also described in human THP-1 macrophage cell line and murine macrophages in response to different stimuli including bacterial toxins, lipoproteins and LPS plus ATP.…”

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confidence: 99%

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The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation

et al. 2007

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Pyroptosis is a caspase-1-dependent inflammatory form of cell death. The adapter protein ASC binds directly to caspase-1 and is critical for caspase-1 activation in response to a broad range of stimuli. To elucidate the mechanism of activation of caspase-1 by ASC and its exact role in macrophage pyroptosis, we performed time-lapse confocal bioimaging analysis on human THP-1 macrophages stably expressing an ASC-GFP fusion protein. We show that stimulation of these cells with several proinflammatory stimuli trigger the formation of a large supramolecular assembly of ASC, termed here pyroptosome. Only one distinct pyroptosome in each stimulated cell is formed, which rapidly recruits and activates caspase-1 resulting in pyroptosis and the release of the intracellular proinflammatory cytokines. The pyroptosome is largely composed of oligomerized ASC dimers. Dimerization of ASC is driven by subphysiological concentrations of potassium as in vitro incubation of purified recombinant ASC in the presence of subphysiological concentrations of potassium induces the assembly of a functional pyroptosome. Furthermore, stimulation of potassium efflux in THP-1 cells with potassium-depleting agents induces formation of the pyroptosome, while increasing potassium concentrations in the culture medium or pharmacological inhibition of this efflux inhibits its assembly. Our results establish that macrophage pyroptosis is mediated by a unique pyroptosome, distinct from the inflammasome.

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Section: Discussionmentioning

confidence: 65%

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confidence: 99%

The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation

et al. 2007

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“…Gram-positive bacteria, or that other host innate immunity factors, such as Nod-like receptors [40][41][42] or p47 GTPases, 23,43 recognize the invading pathogens and signal for autophagy induction.…”

Section: Evasion Of Autophagy By L Monocytogenesmentioning

confidence: 99%

Listeria monocytogenesEvades Killing by Autophagy During Colonization of Host Cells

Birmingham

Canadien²,

Gouin³

et al. 2007

Autophagy

226

206

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Previously published online as an Autophagy E-publication: http://www.landesbioscience.com/journals/autophagy/abstract.php?id=4450 KEY worDsListeria monocytogenes, bacterial invasion, autophagy, innate immunity, lysosome, macrophage. ABBrEViATions ABsTrACTListeria monocytogenes is an intracellular pathogen that is able to colonize the cytosol of macrophages. Here we examined the interaction of this pathogen with autophagy, a host cytosolic degradative pathway that constitutes an important component of innate immunity towards microbial invaders. L. monocytogenes infection induced activation of the autophagy system in macrophages. At 1 h post infection (p.i.), a population of intracellular bacteria (~37%) colocalized with the autophagy marker LC3. These bacteria were within vacuoles and were targeted by autophagy in an LLO-dependent manner. At later stages in infection (by 4 h p.i.), the majority of L. monocytogenes escaped into the cytosol and rapidly replicated. At these times, less than 10% of intracellular bacteria colocalized with LC3. We found that ActA expression was sufficient to prevent autophagy of bacteria in the cytosol of macrophages. Surprisingly, ActA expression was not strictly necessary, indicating that other virulence factors were involved. Accordingly, we also found a role for the bacterial phospholipases, PI-PLC and PC-PLC, in autophagy evasion, as bacteria lacking phospholipase expression were targeted by autophagy at later times in infection. Together, our results demonstrate that L. monocytogenes utilizes multiple mechanisms to avoid destruction by the autophagy system during colonization of macrophages.

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“…Pyroptosis exhibits features common to both apoptosis and necrosis, including nuclear condensation, loss of mitochondrial membrane potential, and membrane swelling (5). It was initially observed in macrophages infected with the intracellular pathogen Salmonella typhimurium (7) but was later found to occur in response to infection with other intracellular pathogens (8,9). Because only a few substrates for caspase-1 have been identified thus far, the mechanism by which caspase-1 kills the cell via pyroptosis remains obscure.…”

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confidence: 99%

The Caspase-1 Digestome Identifies the Glycolysis Pathway as a Target during Infection and Septic Shock

Shao

Yeretssian

Doiron

et al. 2007

Journal of Biological Chemistry

286

252

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Caspase-1 is an essential effector of inflammation, pyroptosis, and septic shock. Few caspase-1 substrates have been identified to date, and these substrates do not account for its wide range of actions. To understand the function of caspase-1, we initiated the systematic identification of its cellular substrates. Using the diagonal gel proteomic approach, we identified 41 proteins that are directly cleaved by caspase-1. Among these were chaperones, cytoskeletal and translation machinery proteins, and proteins involved in immunity. A series of unexpected proteins along the glycolysis pathway were also identified, including aldolase, triose-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, ␣-enolase, and pyruvate kinase. With the exception of the latter, the identified glycolysis enzymes were specifically cleaved in vitro by recombinant caspase-1, but not caspase-3. The enzymatic activity of wild-type glyceraldehyde-3-phosphate dehydrogenase, but not a non-cleavable mutant, was dampened by caspase-1 processing. In vivo, stimuli that fully activated caspase-1, including Salmonella typhimurium infection and septic shock, caused a pronounced processing of these proteins in the macrophage and diaphragm muscle, respectively. Notably, these stimuli inhibited glycolysis in wildtype cells compared with caspase-1-deficient cells. The systematic characterization of caspase-1 substrates identifies the glycolysis pathway as a caspase-1 target and provides new insights into its function during pyroptosis and septic shock.Caspases are aspartate-specific cysteine proteases known for their function in regulating programmed cell death and inflammation. Phylogenetically, they are subdivided into the CED3-related enzymes that initiate and execute cell death and the caspase-1-related proteins that process and mature cytokines, viz. IL-1␤, 2 IL-18, and IL-33. Apoptotic caspases execute cell death through the restricted cleavage of key cellular proteins required to maintain cell viability, resulting in the morphological changes observed during apoptosis, including membrane blebbing, nuclear condensation, and cytoskeletal dismantling (1). Caspase-1 is essential during inflammation because of its role in the activation of cytokine signaling pathways. With the exception of its cytokine substrates, very little is known regarding the spectrum of cellular proteins it targets upon full activation. Similar to other caspases, caspase-1 is found in cells as an inactive precursor and is activated in response to inflammatory triggers, including pathogen-derived molecules, as well as danger signals released from infected or dying cells (2). Caspase-1 activation is achieved in a macromolecular complex known as the inflammasome through its recruitment to a scaffolding molecule generally via the adaptor ASC (3). Scaffolding molecules that activate caspase-1 within the inflammasome belong to the cytosolic Nod-like family of pathogen recognition receptors and include Nalp1-3, Ipaf, and Naip5 (4). More recently, a distinct caspase-1 activat...

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Autophagy and Inflammatory Cell Death, Partners of Innate Immunity

Cited by 48 publications

References 27 publications

The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation

The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation

Listeria monocytogenesEvades Killing by Autophagy During Colonization of Host Cells

The Caspase-1 Digestome Identifies the Glycolysis Pathway as a Target during Infection and Septic Shock

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