Reconstituted NALP1 Inflammasome Reveals Two-Step Mechanism of Caspase-1 Activation

Faustin, Benjamin; Lartigue, Lydia; Bruey, Jean‐Marie; Luciano, Fréderic; Sergienko, Eduard; Bailly-Maître, Béatrice; Volkmann, Niels; Hanein, Dorit; Rouiller, Isabelle; Reed, John C.

doi:10.1016/j.molcel.2007.01.032

Cited by 614 publications

(683 citation statements)

References 34 publications

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“…Indeed, Martinon et al [12] proposed that MDP interacts with the LRR of NALP3 in cell lines and can activate the inflammasome in human macrophages. Similarly, a recent study has suggested that NALP-1 is also an MDP receptor activating caspase-1 [14].…”

Section: Discussionmentioning

confidence: 85%

“…It has been proposed that several of the NLR family members are able to recognize MDP, most notably NOD2, NALP3, and NALP1, and that they execute different functions necessary for cytokine production. In this concept, recognition of MDP by NOD2 would mainly activate NF-jB and thereby gene transcription of pro-IL-1b, whereas NALP3/NALP1-mediated recognition of MDP leads to caspase-1 activation and the subsequent release of the active IL-1b form [12][13][14]. However, there are controversies regarding this mechanism of IL-1b production by MDP.…”

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confidence: 99%

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Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

et al. 2007

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Synthesis and release of pro-inflammatory cytokines, such as IL-1b, play a crucial role in the intestinal inflammation that characterizes Crohn's disease. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are associated with an increased risk of Crohn's disease. Although it is known that NOD2 mediates cytokine responses to muramyl dipeptide (MDP), it is yet unclear whether NOD2 stimulation mediates only transcription of pro-IL-1b mRNA, or whether NOD2 is also involved in the activation of caspase-1 and release of active IL-1b. By investigating the response of MNC from Crohn's disease patients homozygous for the 3020insC NOD2 mutation, we were able to show that NOD2 signaling after stimulation with MDP has a dual effect by activating proIL-1b mRNA transcription and inducing release of bioactive IL-1b. Because NOD2 engagement amplifies TLR stimulation, we investigated whether activation of caspase-1 by MDP is involved in the NOD2/TLR synergism. The synergy in IL-1b production between NOD2 and TLR is mediated at post-translational level in a caspase-1-dependent manner, which indirectly suggests that NOD2 also induces caspase-1 activation. In contrast, the synergy in TNF-a production after stimulation with MDP and LPS is induced at transcriptional level. This demonstrates that both caspase-1-dependent and -independent mechanisms are involved in the synergy between NOD2 and TLR.Introduction NOD-like receptors (NLR) are intracellular receptors for bacterial peptidoglycans, which complement the recognition of pathogen-associated molecular patterns (PAMP) by membrane-bound TLR [1,2]. Nucleotide oligomerization domain 2 (NOD2) is a member of the NACHT-LRR (NLR) receptor family, which recognizes muramyl dipeptide (MDP), the minimal motif of peptidoglycan of both Gram-positive and Gram-negative bacteria [3]. Mutations in the NOD2 gene are associated with Crohn's disease [4,5], but how NOD2 exactly acts in the pathogenesis of this auto-inflammatory disease is unclear [6][7][8]. Therefore, a better understanding of the intracellular events induced by the interaction between NOD2 and peptidoglycan is crucial for both the insight into recognition of Gram-positive pathogens by the innate immune system, and for the pathogenesis of the inflammatory reactions in Crohn's disease. Activation of human mononuclear cells (MNC) by MDP leads to production of pro-inflammatory cytokines, especially IL-1b [7,9]. IL-1b is produced as pro-IL-1b a 31-34-kDa inactive form of the cytokine, which is later cleaved by caspase-1 to the bioactive 17-kDa . This is followed by IL-1b excretion in microvesicles into the extracellular environment [11]. Apparently, MDP is capable of inducing all three steps, but it is unclear whether NOD2 alone or other receptors are involved in one or more of these steps of IL-1b production. It has been proposed that several of the NLR family members are able to recognize MDP, most notably NOD2, NALP3, and NALP1, and that they execute different functions necessary for cytokine production. In this concept, ...

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Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 99%

Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

et al. 2007

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“…Based upon in vitro reconstitution experiments of inflammasome components, it has been suggested that ASC is not essential for inflammasome activation, but acts as an amplifier of inflammasome activity to enhance the innate immune response. 30 In support of this idea is the observation that human NLRP1 forms protein-protein interactions with caspase-1 through its PYD domain in the absence of ASC. 31 However, the NLRP1 protein in mice lacks a functional PYD and therefore, homodimeric interaction between NLRP1 and ASC is not expected.…”

Section: The Nlrp1 Inflammasomementioning

confidence: 97%

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

Vaccari¹,

Dietrich²,

Keane

2014

J Cereb Blood Flow Metab

271

227

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The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1b (IL-1b) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.

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“…Therefore, an analogous mechanism has been proposed for the formation of the NLR inflammasome platform. 14,15 The N-terminal CARD and PYD are the key regions linking the NLR to its downstream functions via oligodimerization with an analogous domain harbored by specific adaptor proteins. NLRs with N-terminal domains that contain CARD usually activate signaling cascades leading to transcription of proinflammatory genes (Figure 1).…”

Section: The Nlr Familymentioning

confidence: 99%

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

2011

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Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1b activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders.

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Reconstituted NALP1 Inflammasome Reveals Two-Step Mechanism of Caspase-1 Activation

Cited by 614 publications

References 34 publications

Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

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