Using rxncon to Develop Rule-Based Models

Romers, Jesper; Thieme, Sebastian; Münzner, Ulrike; Krantz, Marcus

doi:10.1007/978-1-4939-9102-0_4

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…The network reconstruction was performed with a previously developed and demonstrated workflow [9, 14, 15]. Literature curation started from a number of reviews, essentially providing an initial “parts list” in terms of components, processes and signals that can prime or trigger NLRP3.…”

Section: Methodsmentioning

confidence: 99%

A detailed Molecular Network Map and Model of the NLRP3 Inflammasome

Krantz

Eklund

Särndahl

et al. 2023

Preprint

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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.

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Section: Methodsmentioning

confidence: 99%

A detailed Molecular Network Map and Model of the NLRP3 Inflammasome

Krantz

Eklund

Särndahl

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The network reconstruction was performed with a previously developed and demonstrated workflow (16,21,22). Literature curation started from a number of reviews, essentially providing an initial "parts list" in terms of components, processes and signals that can prime or trigger NLRP3.…”

Section: Literature Curation and Network Reconstructionmentioning

confidence: 99%

“…We perform an in-depth literature review and curation to compile the existing mechanistic knowledge on NLRP3 regulation into a formal knowledge base. Briefly, we use an established workflow for reconstruction of signal transduction networks, which relies on iterative literature curation, network validation and gap-filling (16). The goal is to provide a comprehensive mechanistic model, i.e., a model that includes all relevant components and processes of the system under study, and which describes those as an unbroken link of mechanisms and causalities from system input to output.…”

Section: Introductionmentioning

confidence: 99%

A detailed molecular network map and model of the NLRP3 inflammasome

Krantz,

Eklund,

Särndahl

et al. 2023

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

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.

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“…The Boolean network (BN) [1] , [2] , [3] is a mathematical model that is used to represent various biological processes such as gene regulatory networks [4] , [5] , [6] , neural networks [7] , cell cycle control networks [8] , and signal transduction networks [9] , [10] , [11] , [12] . For example, when modeling a gene regulatory network, each node corresponds to a gene and is assigned a Boolean value of 0 (FALSE) or 1 (TRUE), which means the gene is inactive or active, respectively.…”

Section: Introductionmentioning

confidence: 99%