NLRP3 licenses NLRP11 for inflammasome activation in human macrophages

Gangopadhyay, Anu; Devi, Savita; Tenguria, Shivendra; Carrière, Jessica; Nguyen, Hoai-Son; Jäger, Elisabeth; Khatri, H. L.; Chu, Lan H.; Ratsimandresy, Rojo A.; Dorfleutner, Andrea; Stehlik, Christian

doi:10.1038/s41590-022-01220-3

Cited by 32 publications

(26 citation statements)

References 60 publications

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“…Several co-activators of NLRP3 have been identified, including dsDNA-binding protein PKR [ 130 ], guanylate-binding protein GBP5 [ 131 ], receptor for activated C kinase RACK1 [ 132 ], Bruton tyrosine kinase BTK [ 133 , 134 , 135 ], actin-bundling protein L-plastin [ 136 ], stress granule protein DDX3X [ 137 ], NLRP11 [ 138 ], and NIMA-related kinase NEK7 [ 139 , 140 , 141 ]. Among them, NEK7 is an essential component of the NLRP3 inflammasome, but not NLRC4 or AIM2 inflammasomes, and the assembly of NEK7 and NLRP3 requires the K + efflux [ 139 ].…”

Section: Cellular Mechanisms Driving Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Activation and Pharmacological Regulation of Inflammasomes

Chen

2022

Biomolecules

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Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues drives the activation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18 to maturation and gasdermin-D for pore formation, leading to pyroptosis and cytokine release. Inflammasome signaling functions in numerous infectious or sterile inflammatory diseases, including inherited autoinflammatory diseases, metabolic disorders, cardiovascular diseases, cancers, neurodegenerative disorders, and COVID-19. In this review, we summarized current ideas on the organization and activation of inflammasomes, with details on the molecular mechanisms, regulations, and interventions. The recent developments of pharmacological strategies targeting inflammasomes as disease therapeutics were also covered.

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Section: Cellular Mechanisms Driving Nlrp3 Inflammasome Activationmentioning

confidence: 99%

Activation and Pharmacological Regulation of Inflammasomes

Chen

2022

Biomolecules

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“…Further, and as per stress granule formation, NLRP11 has been shown to inhibit NLRP3 inflammasome activation, a phenomenon again attributed to DDX3X sequestration, this time by NLRP11. Perplexingly, NLRP11 was later identified as an essential component required for NLRP3 inflammasome activation ( 60 ). How NLRP11 differentiates between its inhibitory and activating effects on NLRP3 inflammasome activation is currently unclear, however it is possible that DDX3X influences this process.…”

Section: New Players In Nlrp3 Inflammasome Activationmentioning

confidence: 99%

The multifaceted roles of NLRP3-modulating proteins in virus infection

Harris

Borg

2022

Front. Immunol.

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The innate immune response to viruses is critical for the correct establishment of protective adaptive immunity. Amongst the many pathways involved, the NLRP3 [nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3)] inflammasome has received considerable attention, particularly in the context of immunity and pathogenesis during infection with influenza A (IAV) and SARS-CoV-2, the causative agent of COVID-19. Activation of the NLRP3 inflammasome results in the secretion of the proinflammatory cytokines IL-1β and IL-18, commonly coupled with pyroptotic cell death. While this mechanism is protective and key to host defense, aberrant NLRP3 inflammasome activation causes a hyperinflammatory response and excessive release of cytokines, both locally and systemically. Here, we discuss key molecules in the NLRP3 pathway that have also been shown to have significant roles in innate and adaptive immunity to viruses, including DEAD box helicase X-linked (DDX3X), vimentin and macrophage migration inhibitory factor (MIF). We also discuss the clinical opportunities to suppress NLRP3-mediated inflammation and reduce disease severity.

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“…S11). The observed interaction of NLRP11 with caspase-1 may play a role in the recently described contribution of NLRP11 to the NLRP inflammasome ( 26 ). However, NLRP11 function in cLPS-induced cell death of THP-1 macrophages is independent of caspase-1 (Fig.…”

Section: Resultsmentioning

confidence: 73%

Pattern Recognition Receptor for Bacterial Lipopolysaccharide in the Cytosol of Human Macrophages

Rojas-López

Zajac

Wood

et al. 2021

Preprint

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Inflammasomes are cytosolic supramolecular organizing centers that, in response to pathogen-derived molecules and endogenous danger signals, assemble and activate innate immune responses. Bacterial lipopolysaccharide (LPS) is an inflammasome trigger and a major mediator of inflammation during infection, including during the potentially lethal condition sepsis. Activation of most inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing protein (NLRP) or other sensor protein that in turn activates a pro-inflammatory caspase. LPS that accesses the cell cytosol (cLPS) induces cell-autonomous activation of a non-canonical inflammasome that contains caspases-4/5 in humans or caspase-11 in mice1-3. Whereas the NLRPs that sense most pathogen triggers have been identified, no NLRP is known to sense cLPS, which together with the observation that caspases-4, -5, and -11 bind LPS in vitro4, has led to the postulate that inflammasome activation by cLPS occurs independent of an NLRP. Here we show that primate-specific NLRP11 senses cLPS and promotes the activation of caspase-4. We found that in response to infection by each of several gram-negative intracellular bacterial pathogens or to LPS transfection, efficient activation of the non-canonical pathway in human-derived macrophages depends on NLRP11. Further, we found that in both immortalized human-derived macrophages and primary human macrophages, the dependence of the non-canonical pathway on NLRP11 is due to detection of cLPS. Moreover, in cell lysates, NLRP11 binds LPS independently of caspase-4 and binds caspase-4 independently of LPS. Our results demonstrate that NLRP11 senses cLPS and promotes LPS-dependent activation of caspase-4. NLRP11 is a previously missing link in the human non-canonical inflammasome activation pathway.

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NLRP3 licenses NLRP11 for inflammasome activation in human macrophages

Cited by 32 publications

References 60 publications

Activation and Pharmacological Regulation of Inflammasomes

Activation and Pharmacological Regulation of Inflammasomes

The multifaceted roles of NLRP3-modulating proteins in virus infection

Pattern Recognition Receptor for Bacterial Lipopolysaccharide in the Cytosol of Human Macrophages

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