The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1

Thomas, Paul G.; Dash, Pradyot; Aldridge, Jerry R.; Ellebedy, Ali H.; Reynolds, Cory; Funk, Amy; Martin, William J.; Lamkanfi, Mohamed; Webby, Richard J.; Boyd, Kelli L.; Doherty, Peter C.; Kanneganti, Thirumala‐Devi

doi:10.1016/j.immuni.2009.02.006

Cited by 659 publications

(746 citation statements)

References 56 publications

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“…Nlrp3 −/− , ASC −/− , and Casp1 −/− mice backcrossed to C57BL/6 background for at least 10 generations have been described previously (33,34). Mice were housed in a pathogen-free facility and the animal studies were conducted under protocols approved by St. Jude Children's Research Hospital Committee on Use and Care of Animals.…”

Section: Methodsmentioning

confidence: 99%

Inflammasome is a central player in the induction of obesity and insulin resistance

Stienstra

Diepen

Tack

et al. 2011

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

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Inflammation plays a key role in the pathogenesis of obesity. Chronic overfeeding leads to macrophage infiltration in the adipose tissue, resulting in proinflammatory cytokine production. Both microbial and endogenous danger signals trigger assembly of the intracellular innate immune sensor Nlrp3, resulting in caspase-1 activation and production of proinflammatory cytokines IL-1β and IL-18. Here, we showed that mice deficient in Nlrp3, apoptosis-associated speck-like protein, and caspase-1 were resistant to the development of high-fat diet-induced obesity, which correlated with protection from obesityinduced insulin resistance. Furthermore, hepatic triglyceride content, adipocyte size, and macrophage infiltration in adipose tissue were all reduced in mice deficient in inflammasome components. Monocyte chemoattractant protein (MCP)-1 is a key molecule that mediates macrophage infiltration. Indeed, defective inflammasome activation was associated with reduced MCP-1 production in adipose tissue. Furthermore, plasma leptin and resistin that affect energy use and insulin sensitivity were also changed by inflammasome-deficiency. Detailed metabolic and molecular phenotyping demonstrated that the inflammasome controls energy expenditure and adipogenic gene expression during chronic overfeeding. These findings reveal a critical function of the inflammasome in obesity and insulin resistance, and suggest inhibition of the inflammasome as a potential therapeutic strategy.

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Section: Methodsmentioning

confidence: 99%

Inflammasome is a central player in the induction of obesity and insulin resistance

Stienstra

Diepen

Tack

et al. 2011

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

Self Cite

630

521

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show abstract

“…Studies investigating the role of the NLRP3 inflammasome in the development of the adaptive immune response have yielded controversial results; the development of adaptive immunity was found to be mainly dependent on inflammasome activation, but was NLRP3-independent [55,56]. Recently, studies on the mechanism underlying NLRP3 activation during influenza virus infection have suggested that the priming signal for activation of the NLRP3 inflammasome is provided following the recognition of viral RNA by TLR7, with subsequent IL-1b production [57].…”

Section: Rna Virusesmentioning

confidence: 99%

Inflammasomes and its importance in viral infections

León-Juárez²,

et al. 2016

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A complex interplay between pathogen and host determines the immune response during viral infection. A set of cytosolic sensors are expressed by immune cells to detect viral infection. NOD-like receptors (NLRs) comprise a large family of intracellular pattern recognition receptors. Members of the NLR family assemble into large multiprotein complexes, termed inflammasomes, which induce downstream immune responses to specific pathogens, environmental stimuli, and host cell damage. Inflammasomes are composed of cytoplasmic sensor molecules such as NLRP3 or absent in melanoma 2 (AIM2), the adaptor protein ASC (apoptosis-associated speck-like protein containing caspase recruitment domain), and the effector protein procaspase-1. The inflammasome operates as a platform for caspase-1 activation, resulting in caspase-1-dependent proteolytic maturation and secretion of interleukin (IL)-1b and IL-18. This, in turn, activates the expression of other immune genes and facilitates lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Moreover, inflammasomes counter viral replication and remove infected immune cells through an inflammatory cell death, program termed as pyroptosis. As a countermeasure, viral pathogens have evolved virulence factors to antagonise inflammasome pathways. In this review, we discuss the role of inflammasomes in sensing viral infection as well as the evasion strategies that viruses have developed to evade inflammasome-dependent immune responses. This information summarises our understanding of host defence mechanisms against viruses and highlights research areas that can provide new approaches to interfere in the pathogenesis of viral diseases.

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“…Although several independent studies have uncovered a protective function of the inflammasome during viral infections 35,100,101 , others observed that inflammasome activation by certain viruses was mainly crucial for innate and healing response but not for virus control and adaptive immune activation. 102 Thus, the exact mechanism of virus recognition and the possible influence of genetics of inflammasomes on protection from viruses remain unclear.…”

Section: Infectionsmentioning

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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The Intracellular Sensor NLRP3 Mediates Key Innate and Healing Responses to Influenza A Virus via the Regulation of Caspase-1

Cited by 659 publications

References 56 publications

Inflammasome is a central player in the induction of obesity and insulin resistance

Inflammasome is a central player in the induction of obesity and insulin resistance

Inflammasomes and its importance in viral infections

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

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