The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18

Jha, Sushmita; Srivastava, Siddharth Y.; Brickey, W. June; Iocca, Heather A.; Toews, Arrel D.; Morrison, James P.; Chen, Vivian S.; Gris, Denis; Matsushima, Glenn K.; Ting, Jenny P.-Y.

doi:10.1523/jneurosci.4088-10.2010

Cited by 279 publications

(204 citation statements)

References 70 publications

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“…This study and previous ones (6,7,13) showed that Nlrp3 −/− mice are resistant to the development of EAE, suggesting the association of the NLRP3 inflammasome with EAE development. We also showed that Asc −/− mice were resistant to EAE as Nlrp3 −/− mice.…”

Section: Discussionsupporting

confidence: 78%

“…Because it is not clear how the NLRP3 inflammasome enhances EAE, we sought to elucidate the mechanism in this study. Currently, the attenuated Th17 cell responses are suggested to be a major underlying mechanism for the resistance of knockout mice to EAE (13,14). Indeed, a number of studies demonstrated the critical role of Th17 responses in EAE development and the promotion of Th17 cell generation by IL-1β.…”

Section: Discussionmentioning

confidence: 99%

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NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

Inoue¹,

Williams

Gunn³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

230

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The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4 + T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to up-regulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3 −/− and Asc −/− mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

Inoue¹,

Williams

Gunn³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

254

230

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“…Indeed, MLKL-mediated activation of IL-1β has been reported to cause inflammation mediated tissue damage in a model of Staphylococcus aureus infection (43). In addition, there are a growing number of studies that have separately implicated necroptosis or NLRP3 in driving pathology of atherosclerosis (44)(45)(46), multiple sclerosis (47)(48)(49), and ischemia-reperfusion injury of the heart (50, 51) and brain (52)(53)(54). Indeed, in models of kidney ischemiareperfusion injury, both MLKL (42) and NLRP3 (55) deficiency are protective.…”

Section: Discussionmentioning

confidence: 99%

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Conos

Chen

Nardo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

380

298

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Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKLinduced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKLdependent diseases.aspase-dependent apoptotic cell death is required for mammalian development and the prevention of autoimmune and neoplastic diseases. Programmed cell death can also act to eliminate pathogen-infected cells, with recent studies highlighting how targeted apoptosis-inducing anticancer compounds can treat viral and intracellular bacterial infections (1, 2). On the other hand, the recently characterized caspase-independent necroptotic cell death pathway is dispensable for organism development but, like apoptosis, can be triggered to kill cells harboring pathogenic microbes (3). A number of studies have also reported how pathological activation of necroptotic signaling may contribute to diverse disease states, such as ischemia-reperfusion injury, atherosclerosis, and liver disease, presumably through cell death and the release of proinflammatory mediators (4).The execution of necroptosis is dependent on receptor interacting serine-threonine protein kinase 3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and MLKL's association with, and disruption of, plasma membrane integrity (5).In the absence of caspase activit...

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“…Moreover, high cathepsin B activity was detected in CSF samples from patients with neuroinflammatory diseases such as multiple sclerosis (62). Inflammasome activation plays an important role in the three diseases listed above by exacerbating brain inflammation (54,63,64). Therefore, it is conceivable that cathepsin B release and activation may represent a more widespread mechanism for the propagation of inflammasome-dependent immune responses in the brain.…”

Section: Discussionmentioning

confidence: 99%

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

Hoegen

Tremel

Klein

et al. 2011

The Journal of Immunology

195

166

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Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18–binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1β and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1β expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease.

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The Inflammasome Sensor, NLRP3, Regulates CNS Inflammation and Demyelination via Caspase-1 and Interleukin-18

Cited by 279 publications

References 70 publications

NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

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