Innate immunity in Alzheimer's disease Heneka, Michael T; Golenbock, Douglas T; Latz, Eicke
Nature immunology,
03/2015, Letnik:
16, Številka:
3
Journal Article
Recenzirano
Alzheimer's disease (AD) is the world's most common dementing illness, affecting over 150 million patients. Classically AD has been viewed as a neurodegenerative disease of the elderly, characterized ...by the extracellular deposition of misfolded amyloid-β (Aβ) peptide and the intracellular formation of neurofibrillary tangles. Only recently has neuroinflammation emerged as an important component of AD pathology. Experimental, genetic and epidemiological data now indicate a crucial role for activation of the innate immune system as a disease-promoting factor. The sustained formation and deposition of Aβ aggregates causes chronic activation of the immune system and disturbance of microglial clearance functions. Here we review advances in the molecular understanding of the inflammatory response in AD that point to novel therapeutic approaches for the treatment of this devastating disease.
Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in ...neurodegeneration and cognitive decline
. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release
. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice
, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.
Although a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate ...immunity research have led to a better understanding of how existing vaccines work and have informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response, resulting in enhanced protection.
Inflammasomes: too big to miss Stutz, Andrea; Golenbock, Douglas T; Latz, Eicke
The Journal of clinical investigation
119, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Inflammation is the coordinated immune response to harmful stimuli that appear during infections or after tissue damage. Cells of the innate immune system are the central players in mediating ...inflammatory tissue responses. These cells are equipped with an array of signaling receptors that detect foreign molecular substances or altered endogenous molecules that appear under situations of stress. This review provides an overview of recent progress in elucidating the molecular mechanisms that lead to inflammatory reactions. We discuss the current knowledge of the mechanisms leading to the activation of cytoplasmic, multimolecular protein complexes, termed "inflammasomes," which regulate the activity of caspase-1 and the maturation and release of IL-1beta.
Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of ...infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.
Innate immune receptors have a key role in immune surveillance by sensing microorganisms and initiating protective immune responses. However, the innate immune system is a classic 'double-edged ...sword' that can overreact to pathogens, which can have deleterious effects and lead to clinical manifestations. Recent studies have unveiled the complexity of innate immune receptors that function as sensors of Plasmodium spp. in the vertebrate host. This Review highlights the cellular and molecular mechanisms by which Plasmodium infection is sensed by different families of innate immune receptors. We also discuss how these events mediate both host resistance to infection and the pathogenesis of malaria.
Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 ...inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.
The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules ...Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research.
The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of ...the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APP
PSEN1
mice. By contrast, homogenates from brains of APP
PSEN1
mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APP
PSEN1
mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APP
PSEN1
mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.
The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of ...malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. We found that heme, but not porphyrins without iron, activated LPS-primed macrophages promoting the processing of IL-1β dependent on nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3). The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K ⁺ efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.
Significance Heme causes inflammation in sterile and infectious conditions, contributing to the pathogenesis of sickle cell disease, malaria, and sepsis, but the mechanisms by which heme operates are not completely understood. Here we show that heme induces IL-1β processing through the activation of the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages. Our results suggest that among NLRP3 activators, heme has common as well as unique requirements to trigger inflammasome activation. In vivo, hemolysis and heme cause inflammasome activation. Importantly, macrophages, inflammasome components, and IL-1R contribute to hemolysis-induced lethality. These results highlight the potential of understanding the molecular mechanisms by which heme is sensed by innate immune receptors as a way to identify new therapeutic strategies to treat the pathological consequences of hemolytic diseases.
PDF
