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Noncanonical inflammasomes: caspase-11 activation and effector mechanisms.

Broz P, Monack DM - PLoS Pathog. (2013)

View Article: PubMed Central - PubMed

Affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

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Inflammasomes are cytosolic, multiprotein complexes assembled by members of the NOD-like receptor (NLR) and PYHIN protein families in response to pathogen-associated molecular patterns (PAMPs) and danger signals, and serve as activation platforms for caspase-1... Recently, a new noncanonical inflammasome pathway has been described that activates caspase-11, an understudied pro-inflammatory caspase... Microscopic analysis of ASC speck formation suggests that caspase-11 acts upstream of NLRP3, which is consistent with observations reported by the Yuan group, while biochemical enrichment of inflammasomes indicates that caspase-11 is downstream of NLRP3... In conclusion, since caspase-11-mediated cell death lacks associated cytokine maturation, it resembles a programmed lytic cell death more like necroptosis than pyroptosis... Similarly, Rathinam et al. show that LPS treatment or EHEC infections result in lower levels of pro-caspase-11 induction in Trif macrophages... Unexpectedly, their results do not show a contribution of MyD88 to caspase-11 induction, but their study did not directly compare Trif to MyD88/Trif macrophages... We observed that signaling via IFNαR and STAT-1 is crucial for caspase-11 activity in macrophages infected with S. typhimurium , yet this does not result from a lack of pro-caspase-11 expression, since significant levels of pro-caspase-11 are present in cells deficient for components of the type-I-IFN signaling cascade... In contrast to the receptor/scaffold-mediated activation mechanism, Rathinam et al. have suggested that pro-caspase-11 expression is both necessary and sufficient to induce pro-caspase-11 autoactivation (Figure 1C)... However, the usefulness of these systems for the study of caspase activation is limited, since even caspase-1 (which is activated in a receptor-mediated manner) autoactivates in the 293T cell expression system, ... The identification of a specific caspase-11 receptor and/or a bacterial ligand (other than LPS) required for caspase-11 activity would resolve this issue... Finally, the authors showed that caspase-11 might promote the fusion of the L. pneumophila vacuole with lysosomes by modulating actin polymerization through cofilin (Figure 1A)... These results suggest that caspase-11 has other effector mechanisms besides cell death and NLRP3/caspase-1-dependent cytokine maturation... Growth restriction has been shown to control bacterial number in the lungs of mice infected with L. pneumophila ; however, caspase-11-mediated cell death often results in detrimental effects for the host.

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Caspase-11 effector functions and models for caspase-11 activation.(A) Caspase-11 effector functions. Active caspase-11 cooperates with components of the NLRP3 inflammasome to induce caspase-1-dependent maturation of pro-IL-1β and pro-IL-18. It remains to be determined if caspase-11 activates NLRP3 directly or if additional signals are required. Active caspase-11 also induces cell lysis, resulting in the release of danger signals such as IL-1α and HMGB-1. Finally, during L. pneumophila infections, caspase-11 controls phagosome-lysosome fusion through the phosphorylation state of cofilin. (B, C) Two distinct models for caspase-11 activation. (B) Receptor/scaffold-mediated activation. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β and pro-caspase-11. Signaling through Trif and IRF3 induces expression of type-I-IFNs. Type-I-IFN signaling through IFNαR contributes to pro-caspase-11 expression and induces the expression of an uncharacterized receptor/activator of caspase-11. Activation of caspase-11 by this factor might require an additional undefined signal, stemming from the bacterial infection. (C) Autoactivation of pro-caspase-11. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β. Signaling through Trif and IRF3 induces expression of type-I-IFNs, which induces pro-caspase-11 expression. Pro-caspase-11 autoactivates, presumably once a concentration threshold is reached.
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ppat-1003144-g001: Caspase-11 effector functions and models for caspase-11 activation.(A) Caspase-11 effector functions. Active caspase-11 cooperates with components of the NLRP3 inflammasome to induce caspase-1-dependent maturation of pro-IL-1β and pro-IL-18. It remains to be determined if caspase-11 activates NLRP3 directly or if additional signals are required. Active caspase-11 also induces cell lysis, resulting in the release of danger signals such as IL-1α and HMGB-1. Finally, during L. pneumophila infections, caspase-11 controls phagosome-lysosome fusion through the phosphorylation state of cofilin. (B, C) Two distinct models for caspase-11 activation. (B) Receptor/scaffold-mediated activation. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β and pro-caspase-11. Signaling through Trif and IRF3 induces expression of type-I-IFNs. Type-I-IFN signaling through IFNαR contributes to pro-caspase-11 expression and induces the expression of an uncharacterized receptor/activator of caspase-11. Activation of caspase-11 by this factor might require an additional undefined signal, stemming from the bacterial infection. (C) Autoactivation of pro-caspase-11. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β. Signaling through Trif and IRF3 induces expression of type-I-IFNs, which induces pro-caspase-11 expression. Pro-caspase-11 autoactivates, presumably once a concentration threshold is reached.

Mentions: Although both caspase-1 and caspase-11 eventually initiate cell lysis and the release of processed cytokines and danger signals, the hallmarks of inflammasome signaling [5], their underlying mechanisms differ significantly (Figure 1A). Caspase-1 activation by canonical stimuli induces a pro-inflammatory, lytic cell death called pyroptosis. Although caspase-11 activation also induces lysis of the host cell, caspase-11-dependent cell death has features that distinguish it from pyroptosis. Pyroptosis is accompanied by the release of mature, processed cytokines (IL-1β and IL-18) that are secreted by a caspase-1-dependent mechanism called unconventional secretion [6]. In contrast to this, caspase-11 lacks the ability to cleave these cytokines by itself, since macrophages deficient in Nlrp3, ASC, or Casp1 still activate caspase-11 and initiate cell death but do not release mature IL-1β or IL-18. This suggests that caspase-11 acts in conjunction with the NLRP3 inflammasome to promote cytokine maturation [1]. The exact mechanism of this interaction is controversial, which in part could be accounted for by the different assays that have been used to monitor NLRP3 inflammasome assembly. Microscopic analysis of ASC speck formation suggests that caspase-11 acts upstream of NLRP3 [2], which is consistent with observations reported by the Yuan group [7], while biochemical enrichment of inflammasomes indicates that caspase-11 is downstream of NLRP3 [3]. In conclusion, since caspase-11-mediated cell death lacks associated cytokine maturation, it resembles a programmed lytic cell death more like necroptosis than pyroptosis.


Noncanonical inflammasomes: caspase-11 activation and effector mechanisms.

Broz P, Monack DM - PLoS Pathog. (2013)

Caspase-11 effector functions and models for caspase-11 activation.(A) Caspase-11 effector functions. Active caspase-11 cooperates with components of the NLRP3 inflammasome to induce caspase-1-dependent maturation of pro-IL-1β and pro-IL-18. It remains to be determined if caspase-11 activates NLRP3 directly or if additional signals are required. Active caspase-11 also induces cell lysis, resulting in the release of danger signals such as IL-1α and HMGB-1. Finally, during L. pneumophila infections, caspase-11 controls phagosome-lysosome fusion through the phosphorylation state of cofilin. (B, C) Two distinct models for caspase-11 activation. (B) Receptor/scaffold-mediated activation. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β and pro-caspase-11. Signaling through Trif and IRF3 induces expression of type-I-IFNs. Type-I-IFN signaling through IFNαR contributes to pro-caspase-11 expression and induces the expression of an uncharacterized receptor/activator of caspase-11. Activation of caspase-11 by this factor might require an additional undefined signal, stemming from the bacterial infection. (C) Autoactivation of pro-caspase-11. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β. Signaling through Trif and IRF3 induces expression of type-I-IFNs, which induces pro-caspase-11 expression. Pro-caspase-11 autoactivates, presumably once a concentration threshold is reached.
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getmorefigures.php?uid=PMC3585133&req=5

ppat-1003144-g001: Caspase-11 effector functions and models for caspase-11 activation.(A) Caspase-11 effector functions. Active caspase-11 cooperates with components of the NLRP3 inflammasome to induce caspase-1-dependent maturation of pro-IL-1β and pro-IL-18. It remains to be determined if caspase-11 activates NLRP3 directly or if additional signals are required. Active caspase-11 also induces cell lysis, resulting in the release of danger signals such as IL-1α and HMGB-1. Finally, during L. pneumophila infections, caspase-11 controls phagosome-lysosome fusion through the phosphorylation state of cofilin. (B, C) Two distinct models for caspase-11 activation. (B) Receptor/scaffold-mediated activation. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β and pro-caspase-11. Signaling through Trif and IRF3 induces expression of type-I-IFNs. Type-I-IFN signaling through IFNαR contributes to pro-caspase-11 expression and induces the expression of an uncharacterized receptor/activator of caspase-11. Activation of caspase-11 by this factor might require an additional undefined signal, stemming from the bacterial infection. (C) Autoactivation of pro-caspase-11. Detection of Gram-negative bacteria by TLR4 results in the activation of NFκB and subsequent expression of pro-IL-1β. Signaling through Trif and IRF3 induces expression of type-I-IFNs, which induces pro-caspase-11 expression. Pro-caspase-11 autoactivates, presumably once a concentration threshold is reached.
Mentions: Although both caspase-1 and caspase-11 eventually initiate cell lysis and the release of processed cytokines and danger signals, the hallmarks of inflammasome signaling [5], their underlying mechanisms differ significantly (Figure 1A). Caspase-1 activation by canonical stimuli induces a pro-inflammatory, lytic cell death called pyroptosis. Although caspase-11 activation also induces lysis of the host cell, caspase-11-dependent cell death has features that distinguish it from pyroptosis. Pyroptosis is accompanied by the release of mature, processed cytokines (IL-1β and IL-18) that are secreted by a caspase-1-dependent mechanism called unconventional secretion [6]. In contrast to this, caspase-11 lacks the ability to cleave these cytokines by itself, since macrophages deficient in Nlrp3, ASC, or Casp1 still activate caspase-11 and initiate cell death but do not release mature IL-1β or IL-18. This suggests that caspase-11 acts in conjunction with the NLRP3 inflammasome to promote cytokine maturation [1]. The exact mechanism of this interaction is controversial, which in part could be accounted for by the different assays that have been used to monitor NLRP3 inflammasome assembly. Microscopic analysis of ASC speck formation suggests that caspase-11 acts upstream of NLRP3 [2], which is consistent with observations reported by the Yuan group [7], while biochemical enrichment of inflammasomes indicates that caspase-11 is downstream of NLRP3 [3]. In conclusion, since caspase-11-mediated cell death lacks associated cytokine maturation, it resembles a programmed lytic cell death more like necroptosis than pyroptosis.

View Article: PubMed Central - PubMed

Affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, Basel, Switzerland.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Inflammasomes are cytosolic, multiprotein complexes assembled by members of the NOD-like receptor (NLR) and PYHIN protein families in response to pathogen-associated molecular patterns (PAMPs) and danger signals, and serve as activation platforms for caspase-1... Recently, a new noncanonical inflammasome pathway has been described that activates caspase-11, an understudied pro-inflammatory caspase... Microscopic analysis of ASC speck formation suggests that caspase-11 acts upstream of NLRP3, which is consistent with observations reported by the Yuan group, while biochemical enrichment of inflammasomes indicates that caspase-11 is downstream of NLRP3... In conclusion, since caspase-11-mediated cell death lacks associated cytokine maturation, it resembles a programmed lytic cell death more like necroptosis than pyroptosis... Similarly, Rathinam et al. show that LPS treatment or EHEC infections result in lower levels of pro-caspase-11 induction in Trif macrophages... Unexpectedly, their results do not show a contribution of MyD88 to caspase-11 induction, but their study did not directly compare Trif to MyD88/Trif macrophages... We observed that signaling via IFNαR and STAT-1 is crucial for caspase-11 activity in macrophages infected with S. typhimurium , yet this does not result from a lack of pro-caspase-11 expression, since significant levels of pro-caspase-11 are present in cells deficient for components of the type-I-IFN signaling cascade... In contrast to the receptor/scaffold-mediated activation mechanism, Rathinam et al. have suggested that pro-caspase-11 expression is both necessary and sufficient to induce pro-caspase-11 autoactivation (Figure 1C)... However, the usefulness of these systems for the study of caspase activation is limited, since even caspase-1 (which is activated in a receptor-mediated manner) autoactivates in the 293T cell expression system, ... The identification of a specific caspase-11 receptor and/or a bacterial ligand (other than LPS) required for caspase-11 activity would resolve this issue... Finally, the authors showed that caspase-11 might promote the fusion of the L. pneumophila vacuole with lysosomes by modulating actin polymerization through cofilin (Figure 1A)... These results suggest that caspase-11 has other effector mechanisms besides cell death and NLRP3/caspase-1-dependent cytokine maturation... Growth restriction has been shown to control bacterial number in the lungs of mice infected with L. pneumophila ; however, caspase-11-mediated cell death often results in detrimental effects for the host.

Show MeSH
Related in: MedlinePlus