NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

Freeman, Leslie; Guo, Haitao; David, Clément N.; Brickey, W. June; Jha, Sushmita; Ting, Jenny P.Y.

doi:10.1084/jem.20150237

Cited by 331 publications

(285 citation statements)

References 96 publications

Supporting

Mentioning

263

Contrasting

Unclassified

Order By: Relevance

“…However, microglia are also critical for an extensive and often sustainable (up to years) generation of cytokines (for example, IL-1β and IL-6) and ROS, which in turn recruit neutrophils and blood monocytes-macrophages to the injured area 103,105,108 . Furthermore, complement 109 or lysophosphatidylcholine activates inflammasomes in microglia or astrocytes soon after TBI and during neuro-inflammation 110 . After exposure to IL-1β, astrocytes rapidly generate immune signals in the form of extracellular vesicles dispatched to the periphery, which results in the further recruitment of neutrophils and systemic release of cytokines 111 .…”

Section: Cerebral and Extracerebral Challenges To The Innate Immune Smentioning

confidence: 99%

Innate immune responses to trauma

2018

View full text Add to dashboard Cite

Trauma can affect any individual at any location and at any time over a lifespan. The disruption of macrobarriers and microbarriers induces instant activation of innate immunity. The subsequent complex response, designed to limit further damage and induce healing, also represents a major driver of complications and fatal outcome after injury. This Review aims to provide basic concepts about the posttraumatic response and is focused on the interactive events of innate immunity at frequent sites of injury: the endothelium at large, and sites within the lungs, inside and outside the brain and at the gut barrier.

show abstract

Section: Cerebral and Extracerebral Challenges To The Innate Immune Smentioning

confidence: 99%

Innate immune responses to trauma

2018

View full text Add to dashboard Cite

show abstract

“…Therefore, insights into the regulation of NLRP3 in macrophages may not necessarily reflect the same regulatory dynamics of NLRP3 in microglia, especially in regards to their tendencies for pyroptosis or non-pyroptotic inflammation. One study found that murine microglia primed with LPS and then stimulated with the DAMP lysophosphatidylcholine led to NLRP3 mediated inflammation; however, cytotoxicity of microglia was not dependent on NLRP3 canonical or non-canonical activation (Freeman et al, 2017). An additional study using murine microglia also found that a two-step activation paradigm regulates NLRP3 inflammasome activation in response to TLR4 stimulation (Sanz and Di Virgilio, 2000).…”

Section: Priming and Activation Of The Nlrp3 Inflammasomementioning

confidence: 99%

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Herman

Pasinetti

2018

Brain, Behavior, and Immunity

100

View full text Add to dashboard Cite

The production of inflammatory proteins by the innate immune system is a tightly orchestrated procedure that allows the body to efficiently respond to exogenous and endogenous threats. Recently, accumulating evidence has indicated that disturbances in the inflammatory response system not only provoke autoimmune disorders, but also can have deleterious effects on neuronal function and mental health. As inflammation in the brain is primarily mediated by microglia, there has been an expanding focus on the mechanisms through which these cells initiate and propagate neuroinflammation. Microglia can enter persistently active states upon their initial recognition of an environmental stressor and are thereafter prone to elicit amplified and persistent inflammatory responses following subsequent exposures to stressors. A recent focus on why primed microglia cells are susceptible to environmental insults has been the NLRP3 inflammasome. Its function within the innate immune system is regulated in such a manner that supports a role for the complex in gating neuroinflammatory responses. The activation of NLRP3 inflammasome in microglia results in the cleavage of zymogen inflammatory interleukins into functional forms that elicit a number of consequential effects in the local neuronal environment. There is evidence to support the principle that within primed neuroimmune systems a lowered threshold for NLRP3 activation can cause persistent neuroinflammation or the amplified production of inflammatory cytokines, such as IL-1β and IL-18. Over the course of an individual's lifetime, persistent neuroinflammation can subsequently lead to the pathophysiological signatures that define psychological disorders. Therefore, targeting the NLRP3 inflammasome complex may represent an innovative and consequential approach to limit neuroinflammatory states in psychiatric disorders, such as major depressive disorder.

show abstract

“…The list of NLRP3 activators is extensive and includes Gram‐positive and ‐negative bacteria, bacterial toxins, DNA and RNA viruses, fungi, and protozoa . In addition, NLRP3 can sense a variety of DAMPs, including ATP, uric acid crystals, silica crystals, saturated fatty acids, asbestos, extracellular histones, lysophosphatidylcholine, aluminum hydroxide, and bee venom . It is currently hypothesized that rather than direct binding of NLRP3 to the ligand, the repertoire of diverse ligands triggers a common set of cellular events that culminate in the activation of NLRP3.…”

Section: Canonical Nlrp3 Inflammasomementioning

confidence: 99%

“…For instance, mouse macrophages exposed to hyperosmotic stress produce IL‐1β in a manner dependent on both NLRC4 and NLRP3 inflammasome activity . Likewise, NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes in response to the DAMP lysophosphatidylcholine . Finally, in a rodent model of stroke, the NLRC4 and AIM2 inflammasomes contribute to ischemic brain injury in a manner that required ASC but not NLRP3 …”

Section: Naip‐nlrc4 Inflammasomementioning

confidence: 99%

Molecular mechanisms of inflammasome signaling

Mathur

Hayward

Man

2017

Journal of Leukocyte Biology

153

123

View full text Add to dashboard Cite

The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1β and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome.

show abstract

NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes

Cited by 331 publications

References 96 publications

Innate immune responses to trauma

Innate immune responses to trauma

Principles of inflammasome priming and inhibition: Implications for psychiatric disorders

Molecular mechanisms of inflammasome signaling

Contact Info

Product

Resources

About