The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogen‐derived or damage‐derived molecular patterns, pro‐caspase‐1, and an adaptor called ...ASC (apoptotic speck containing protein with a CARD), which results in caspase‐1 maturation. Caspase‐1 then mediates the release of pro‐inflammatory cytokines such as IL‐1β and IL‐18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis.
We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro‐caspase‐1 to the mature form of caspase‐1 which cleaves pro‐IL‐1β and pro‐IL‐18 into their mature forms of IL‐1β and IL‐18.
We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro‐caspase‐1 to the mature form of caspase‐1 which cleaves pro‐IL‐1β and pro‐IL‐18 into their mature forms of IL‐1β and IL‐18.
This article is part of the Special Issue “Neuroinflammation – A Two Way Street Directing CNS Injury and Repair”.
Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer's disease. Neuroinflammation is sterile, as damage-associated ...molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance,
and
mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis.
"It is my sincere hope that this volume will be much read and reflected upon by new generations of American students of prehistoric archaeologists. Freeman's career is a model for long-term ...international collaboration, theoretical eclecticism, the centrality of field research, and the ability to 'dream big,' but with a commonsense approach to the record and its limitations." Lawrence Guy Straus, Journal of Anthropological Research
L.G. Freeman is a major scholar of Old World Paleolithic prehistory and a self-described "behavioral paleoanthropologist." Anthropology without Informants is a collection of previously published ...papers by this preeminent archaeologist, representing a cross section of his contributions to Old Work Paleolithic prehistory and archaeological theory. A socio-cultural anthropologist who became a behavioral paleoanthropologist late in his career, Freeman took a unique approach, employing statistical or mathematical techniques in his analysis of archaeological data. All the papers in this collection blend theoretical statements with the archeological facts they are intended to help the reader understand.Although he taught at the University of Chicago for the span of his 40-year career, Freeman is not well-known among Anglophone scholars, because his primary fieldwork and publishing occurred in Cantabrian, Spain. However, he has been a major player in Paleolithic prehistory, and this volume will introduce his work to more American Archaeologists.This collection brings the work of an expert scholar, to a broad audience, and will be of interest to archaeologists, their students, and lay readers interested in the Paleolithic era.
The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells
. It consists of an innate immune receptor/sensor, ...pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells
. Here we show that the DNA-binding inflammasome receptor AIM2
has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (T
) cells. AIM2 is highly expressed by both human and mouse T
cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with T
cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in T
cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of T
cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of T
cells.
Abstract
The inflammasome is implicated in many inflammatory diseases including neurological diseases but has been primarily studied in the macrophage-myeloid lineage. Here we demonstrate a ...physiologic role for nucleotide-binding domain, leucine-rich repeat, CARD domain containing proteins, NLRC4 and NLRP3, in brain astrocytes and microglia under the sterile neuroinflammation condition. In vitro, lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits an inflammasome activation dependent on both NLRC4 and NLRP3 in microglia and astrocytes, which are central players in neuroinflammation. Canonical inflammasome components ASC and caspase-1 but not non-canonical inflammasome component caspase-11 is required for LPC-activated inflammasome. Mechanistically, LPC-activated inflammasome also requires cathepsin B protease, calcium mobilization and potassium efflux. In an in vivo cuprizone model of neuroinflammation and demyelination, we found only mice lacking both Nlrc4 and Nlrp3 genes show the significant reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor, G2A, while multiple sclerosis (MS) patient samples show increased G2A. These results reveal that both NLRC4 and NLRP3 are involved in activating LPC-induced inflammasome and are important in astrogliosis and microglial accumulation in a neurological disease model.
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