A detailed molecular network map and model of the NLRP3 inflammasome
The NLRP3 inflammasome is a key regulator of inflammation that responds to a broad range of stimuli. The exact mechanism of activation has not been determined, but there is a consensus on cellular potassium efflux as a major common denominator. Once NLRP3 is activated, it forms high-order complexes...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233680/full |
| _version_ | 1797519430557630464 |
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| author | Marcus Krantz Marcus Krantz Daniel Eklund Daniel Eklund Eva Särndahl Eva Särndahl Alexander Hedbrant Alexander Hedbrant |
| author_facet | Marcus Krantz Marcus Krantz Daniel Eklund Daniel Eklund Eva Särndahl Eva Särndahl Alexander Hedbrant Alexander Hedbrant |
| author_sort | Marcus Krantz |
| collection | DOAJ |
| description | The NLRP3 inflammasome is a key regulator of inflammation that responds to a broad range of stimuli. The exact mechanism of activation has not been determined, but there is a consensus on cellular potassium efflux as a major common denominator. Once NLRP3 is activated, it forms high-order complexes together with NEK7 that trigger aggregation of ASC into specks. Typically, there is only one speck per cell, consistent with the proposal that specks form – or end up at – the centrosome. ASC polymerisation in turn triggers caspase-1 activation, leading to maturation and release of IL-1β and pyroptosis, i.e., highly inflammatory cell death. Several gain-of-function mutations in the NLRP3 inflammasome have been suggested to induce spontaneous activation of NLRP3 and hence contribute to development and disease severity in numerous autoinflammatory and autoimmune diseases. Consequently, the NLRP3 inflammasome is of significant clinical interest, and recent attention has drastically improved our insight in the range of involved triggers and mechanisms of signal transduction. However, despite recent progress in knowledge, a clear and comprehensive overview of how these mechanisms interplay to shape the system level function is missing from the literature. Here, we provide such an overview as a resource to researchers working in or entering the field, as well as a computational model that allows for evaluating and explaining the function of the NLRP3 inflammasome system from the current molecular knowledge. We present a detailed reconstruction of the molecular network surrounding the NLRP3 inflammasome, which account for each specific reaction and the known regulatory constraints on each event as well as the mechanisms of drug action and impact of genetics when known. Furthermore, an executable model from this network reconstruction is generated with the aim to be used to explain NLRP3 activation from priming and activation to the maturation and release of IL-1β and IL-18. Finally, we test this detailed mechanistic model against data on the effect of different modes of inhibition of NLRP3 assembly. While the exact mechanisms of NLRP3 activation remains elusive, the literature indicates that the different stimuli converge on a single activation mechanism that is additionally controlled by distinct (positive or negative) priming and licensing events through covalent modifications of the NLRP3 molecule. Taken together, we present a compilation of the literature knowledge on the molecular mechanisms on NLRP3 activation, a detailed mechanistic model of NLRP3 activation, and explore the convergence of diverse NLRP3 activation stimuli into a single input mechanism. |
| first_indexed | 2024-03-10T07:42:41Z |
| format | Article |
| id | doaj.art-88b02ba1336144bc8ce8ca3d0d44058c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-10T07:42:41Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-88b02ba1336144bc8ce8ca3d0d44058c2023-11-22T12:57:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12336801233680A detailed molecular network map and model of the NLRP3 inflammasomeMarcus Krantz0Marcus Krantz1Daniel Eklund2Daniel Eklund3Eva Särndahl4Eva Särndahl5Alexander Hedbrant6Alexander Hedbrant7School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, SwedenInflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, SwedenSchool of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, SwedenInflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, SwedenSchool of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, SwedenInflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, SwedenSchool of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, SwedenInflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, SwedenThe NLRP3 inflammasome is a key regulator of inflammation that responds to a broad range of stimuli. The exact mechanism of activation has not been determined, but there is a consensus on cellular potassium efflux as a major common denominator. Once NLRP3 is activated, it forms high-order complexes together with NEK7 that trigger aggregation of ASC into specks. Typically, there is only one speck per cell, consistent with the proposal that specks form – or end up at – the centrosome. ASC polymerisation in turn triggers caspase-1 activation, leading to maturation and release of IL-1β and pyroptosis, i.e., highly inflammatory cell death. Several gain-of-function mutations in the NLRP3 inflammasome have been suggested to induce spontaneous activation of NLRP3 and hence contribute to development and disease severity in numerous autoinflammatory and autoimmune diseases. Consequently, the NLRP3 inflammasome is of significant clinical interest, and recent attention has drastically improved our insight in the range of involved triggers and mechanisms of signal transduction. However, despite recent progress in knowledge, a clear and comprehensive overview of how these mechanisms interplay to shape the system level function is missing from the literature. Here, we provide such an overview as a resource to researchers working in or entering the field, as well as a computational model that allows for evaluating and explaining the function of the NLRP3 inflammasome system from the current molecular knowledge. We present a detailed reconstruction of the molecular network surrounding the NLRP3 inflammasome, which account for each specific reaction and the known regulatory constraints on each event as well as the mechanisms of drug action and impact of genetics when known. Furthermore, an executable model from this network reconstruction is generated with the aim to be used to explain NLRP3 activation from priming and activation to the maturation and release of IL-1β and IL-18. Finally, we test this detailed mechanistic model against data on the effect of different modes of inhibition of NLRP3 assembly. While the exact mechanisms of NLRP3 activation remains elusive, the literature indicates that the different stimuli converge on a single activation mechanism that is additionally controlled by distinct (positive or negative) priming and licensing events through covalent modifications of the NLRP3 molecule. Taken together, we present a compilation of the literature knowledge on the molecular mechanisms on NLRP3 activation, a detailed mechanistic model of NLRP3 activation, and explore the convergence of diverse NLRP3 activation stimuli into a single input mechanism.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233680/fullNLRP3NLRP3 triggersinflammasomerxnconmechanistic modelosmotic stress |
| spellingShingle | Marcus Krantz Marcus Krantz Daniel Eklund Daniel Eklund Eva Särndahl Eva Särndahl Alexander Hedbrant Alexander Hedbrant A detailed molecular network map and model of the NLRP3 inflammasome Frontiers in Immunology NLRP3 NLRP3 triggers inflammasome rxncon mechanistic model osmotic stress |
| title | A detailed molecular network map and model of the NLRP3 inflammasome |
| title_full | A detailed molecular network map and model of the NLRP3 inflammasome |
| title_fullStr | A detailed molecular network map and model of the NLRP3 inflammasome |
| title_full_unstemmed | A detailed molecular network map and model of the NLRP3 inflammasome |
| title_short | A detailed molecular network map and model of the NLRP3 inflammasome |
| title_sort | detailed molecular network map and model of the nlrp3 inflammasome |
| topic | NLRP3 NLRP3 triggers inflammasome rxncon mechanistic model osmotic stress |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1233680/full |
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