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The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease.

Richards RI, Robertson SA, O'Keefe LV, Fornarino D, Scott A, Lardelli M, Baune BT - Front Neurosci (2016)

Bottom Line: If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site.Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes.Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Evolution, Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide Adelaide, SA, Australia.

ABSTRACT
Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an "intelligent system," in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death.

No MeSH data available.


Related in: MedlinePlus

Simplified schematic of signaling junctions that integrate the recognition of pathogen, host or environmentally derived DAMPs and dAMPs by their cognate receptors. Viral or host derived nucleic acids are recognized by several PRR families according to distinct structural characteristics and their location. cGAS generates second messenger cGAMP to activate STING-dependent signaling (Hornung et al., 2014). Other cytoplasmic DNA sensors, such as IFI16, converge on this pathway (Goubau et al., 2010). RIG-I has dual functions in inducing nuclear translocation of transcription factors such as NF-κB and IRF-3/7 through MAVS (Yoneyama et al., 2016) and MAVS-independent inflammasome activation (Poeck et al., 2010). Like RIG-I, inflammasome forming PRRs AIM2 and NLRP1/3 direct procytokine conversion by activating caspase-1 (Kim et al., 2016; Thaiss et al., 2016; in response to stimuli such as bacteria-derived MDP or toxins (Wen et al., 2013). Transcription factors NF-κB, AP-1, and IRF-3/7 can also translocate to the nucleus following activation of the endosomal TLRs which signal through either Myd88 or TRIF. Membrane bound TLR2/4 innervate these pathways on detecting host derived dAMPs such as HSPs and MSU (Gelderblom et al., 2015). Binding of pro-inflammatory ligands including AGEs, S100/calgranulin, amphoterin (HMGB1), and amyloid beta-peptide to RAGE, the receptor of advanced glycation end-products, triggers an increase in proinflammatory molecules, oxidative stressors and cytokines (Ray et al., 2015). HMGB1 is a diverse PRR activator (Harris et al., 2012). TLR3-mediated necrosis is via TRIF (Kaiser et al., 2013). A table of DAMPs/dAMPs and their respective PRRs is included in Supplementary Section. PRR, pattern recognition receptor; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; STING, stimulator of IFN genes; IFI16, IFN-Υ-inducible protein 16; RIG-I, retinioc acid inducible gene-I; NF-κB, nuclear factor kappa B; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; AIM2, absent in melanoma 2; NLRP, NOD like receptor, pyrin domain containing 1 and 3; MDP, muramyl-dipeptide; AP1, activator protein 1; TLRs, Toll-like receptors; Myd88, myeloid differentiation primary response 88; TRIF, Toll/interleukin-1 receptor domain containing adapter-inducing interferon-β; DAMPs, danger-associated molecular patterns; dAMPs, damage-associated molecular patterns; AGEs, advanced glycation end products; HSPs, heat-shock proteins; MSU, monosodium urate.
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Figure 1: Simplified schematic of signaling junctions that integrate the recognition of pathogen, host or environmentally derived DAMPs and dAMPs by their cognate receptors. Viral or host derived nucleic acids are recognized by several PRR families according to distinct structural characteristics and their location. cGAS generates second messenger cGAMP to activate STING-dependent signaling (Hornung et al., 2014). Other cytoplasmic DNA sensors, such as IFI16, converge on this pathway (Goubau et al., 2010). RIG-I has dual functions in inducing nuclear translocation of transcription factors such as NF-κB and IRF-3/7 through MAVS (Yoneyama et al., 2016) and MAVS-independent inflammasome activation (Poeck et al., 2010). Like RIG-I, inflammasome forming PRRs AIM2 and NLRP1/3 direct procytokine conversion by activating caspase-1 (Kim et al., 2016; Thaiss et al., 2016; in response to stimuli such as bacteria-derived MDP or toxins (Wen et al., 2013). Transcription factors NF-κB, AP-1, and IRF-3/7 can also translocate to the nucleus following activation of the endosomal TLRs which signal through either Myd88 or TRIF. Membrane bound TLR2/4 innervate these pathways on detecting host derived dAMPs such as HSPs and MSU (Gelderblom et al., 2015). Binding of pro-inflammatory ligands including AGEs, S100/calgranulin, amphoterin (HMGB1), and amyloid beta-peptide to RAGE, the receptor of advanced glycation end-products, triggers an increase in proinflammatory molecules, oxidative stressors and cytokines (Ray et al., 2015). HMGB1 is a diverse PRR activator (Harris et al., 2012). TLR3-mediated necrosis is via TRIF (Kaiser et al., 2013). A table of DAMPs/dAMPs and their respective PRRs is included in Supplementary Section. PRR, pattern recognition receptor; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; STING, stimulator of IFN genes; IFI16, IFN-Υ-inducible protein 16; RIG-I, retinioc acid inducible gene-I; NF-κB, nuclear factor kappa B; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; AIM2, absent in melanoma 2; NLRP, NOD like receptor, pyrin domain containing 1 and 3; MDP, muramyl-dipeptide; AP1, activator protein 1; TLRs, Toll-like receptors; Myd88, myeloid differentiation primary response 88; TRIF, Toll/interleukin-1 receptor domain containing adapter-inducing interferon-β; DAMPs, danger-associated molecular patterns; dAMPs, damage-associated molecular patterns; AGEs, advanced glycation end products; HSPs, heat-shock proteins; MSU, monosodium urate.

Mentions: The host defense system operates in an environment comprising a complex mixture of molecules - some pose a threat while others are either harmless or beneficial. Recognition of threatening molecules occurs on the basis of their molecular pattern (Figure 1).


The Enemy within: Innate Surveillance-Mediated Cell Death, the Common Mechanism of Neurodegenerative Disease.

Richards RI, Robertson SA, O'Keefe LV, Fornarino D, Scott A, Lardelli M, Baune BT - Front Neurosci (2016)

Simplified schematic of signaling junctions that integrate the recognition of pathogen, host or environmentally derived DAMPs and dAMPs by their cognate receptors. Viral or host derived nucleic acids are recognized by several PRR families according to distinct structural characteristics and their location. cGAS generates second messenger cGAMP to activate STING-dependent signaling (Hornung et al., 2014). Other cytoplasmic DNA sensors, such as IFI16, converge on this pathway (Goubau et al., 2010). RIG-I has dual functions in inducing nuclear translocation of transcription factors such as NF-κB and IRF-3/7 through MAVS (Yoneyama et al., 2016) and MAVS-independent inflammasome activation (Poeck et al., 2010). Like RIG-I, inflammasome forming PRRs AIM2 and NLRP1/3 direct procytokine conversion by activating caspase-1 (Kim et al., 2016; Thaiss et al., 2016; in response to stimuli such as bacteria-derived MDP or toxins (Wen et al., 2013). Transcription factors NF-κB, AP-1, and IRF-3/7 can also translocate to the nucleus following activation of the endosomal TLRs which signal through either Myd88 or TRIF. Membrane bound TLR2/4 innervate these pathways on detecting host derived dAMPs such as HSPs and MSU (Gelderblom et al., 2015). Binding of pro-inflammatory ligands including AGEs, S100/calgranulin, amphoterin (HMGB1), and amyloid beta-peptide to RAGE, the receptor of advanced glycation end-products, triggers an increase in proinflammatory molecules, oxidative stressors and cytokines (Ray et al., 2015). HMGB1 is a diverse PRR activator (Harris et al., 2012). TLR3-mediated necrosis is via TRIF (Kaiser et al., 2013). A table of DAMPs/dAMPs and their respective PRRs is included in Supplementary Section. PRR, pattern recognition receptor; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; STING, stimulator of IFN genes; IFI16, IFN-Υ-inducible protein 16; RIG-I, retinioc acid inducible gene-I; NF-κB, nuclear factor kappa B; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; AIM2, absent in melanoma 2; NLRP, NOD like receptor, pyrin domain containing 1 and 3; MDP, muramyl-dipeptide; AP1, activator protein 1; TLRs, Toll-like receptors; Myd88, myeloid differentiation primary response 88; TRIF, Toll/interleukin-1 receptor domain containing adapter-inducing interferon-β; DAMPs, danger-associated molecular patterns; dAMPs, damage-associated molecular patterns; AGEs, advanced glycation end products; HSPs, heat-shock proteins; MSU, monosodium urate.
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Figure 1: Simplified schematic of signaling junctions that integrate the recognition of pathogen, host or environmentally derived DAMPs and dAMPs by their cognate receptors. Viral or host derived nucleic acids are recognized by several PRR families according to distinct structural characteristics and their location. cGAS generates second messenger cGAMP to activate STING-dependent signaling (Hornung et al., 2014). Other cytoplasmic DNA sensors, such as IFI16, converge on this pathway (Goubau et al., 2010). RIG-I has dual functions in inducing nuclear translocation of transcription factors such as NF-κB and IRF-3/7 through MAVS (Yoneyama et al., 2016) and MAVS-independent inflammasome activation (Poeck et al., 2010). Like RIG-I, inflammasome forming PRRs AIM2 and NLRP1/3 direct procytokine conversion by activating caspase-1 (Kim et al., 2016; Thaiss et al., 2016; in response to stimuli such as bacteria-derived MDP or toxins (Wen et al., 2013). Transcription factors NF-κB, AP-1, and IRF-3/7 can also translocate to the nucleus following activation of the endosomal TLRs which signal through either Myd88 or TRIF. Membrane bound TLR2/4 innervate these pathways on detecting host derived dAMPs such as HSPs and MSU (Gelderblom et al., 2015). Binding of pro-inflammatory ligands including AGEs, S100/calgranulin, amphoterin (HMGB1), and amyloid beta-peptide to RAGE, the receptor of advanced glycation end-products, triggers an increase in proinflammatory molecules, oxidative stressors and cytokines (Ray et al., 2015). HMGB1 is a diverse PRR activator (Harris et al., 2012). TLR3-mediated necrosis is via TRIF (Kaiser et al., 2013). A table of DAMPs/dAMPs and their respective PRRs is included in Supplementary Section. PRR, pattern recognition receptor; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; STING, stimulator of IFN genes; IFI16, IFN-Υ-inducible protein 16; RIG-I, retinioc acid inducible gene-I; NF-κB, nuclear factor kappa B; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral signaling protein; AIM2, absent in melanoma 2; NLRP, NOD like receptor, pyrin domain containing 1 and 3; MDP, muramyl-dipeptide; AP1, activator protein 1; TLRs, Toll-like receptors; Myd88, myeloid differentiation primary response 88; TRIF, Toll/interleukin-1 receptor domain containing adapter-inducing interferon-β; DAMPs, danger-associated molecular patterns; dAMPs, damage-associated molecular patterns; AGEs, advanced glycation end products; HSPs, heat-shock proteins; MSU, monosodium urate.
Mentions: The host defense system operates in an environment comprising a complex mixture of molecules - some pose a threat while others are either harmless or beneficial. Recognition of threatening molecules occurs on the basis of their molecular pattern (Figure 1).

Bottom Line: If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site.Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes.Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Evolution, Centre for Molecular Pathology, School of Biological Sciences, The University of Adelaide Adelaide, SA, Australia.

ABSTRACT
Neurodegenerative diseases comprise an array of progressive neurological disorders all characterized by the selective death of neurons in the central nervous system. Although, rare (familial) and common (sporadic) forms can occur for the same disease, it is unclear whether this reflects several distinct pathogenic pathways or the convergence of different causes into a common form of nerve cell death. Remarkably, neurodegenerative diseases are increasingly found to be accompanied by activation of the innate immune surveillance system normally associated with pathogen recognition and response. Innate surveillance is the cell's quality control system for the purpose of detecting such danger signals and responding in an appropriate manner. Innate surveillance is an "intelligent system," in that the manner of response is relevant to the magnitude and duration of the threat. If possible, the threat is dealt with within the cell in which it is detected, by degrading the danger signal(s) and restoring homeostasis. If this is not successful then an inflammatory response is instigated that is aimed at restricting the spread of the threat by elevating degradative pathways, sensitizing neighboring cells, and recruiting specialized cell types to the site. If the danger signal persists, then the ultimate response can include not only the programmed cell death of the original cell, but the contents of this dead cell can also bring about the death of adjacent sensitized cells. These responses are clearly aimed at destroying the ability of the detected pathogen to propagate and spread. Innate surveillance comprises intracellular, extracellular, non-cell autonomous and systemic processes. Recent studies have revealed how multiple steps in these processes involve proteins that, through their mutation, have been linked to many familial forms of neurodegenerative disease. This suggests that individuals harboring these mutations may have an amplified response to innate-mediated damage in neural tissues, and renders innate surveillance mediated cell death a plausible common pathogenic pathway responsible for neurodegenerative diseases, in both familial and sporadic forms. Here we have assembled evidence in favor of the hypothesis that neurodegenerative disease is the cumulative result of chronic activation of the innate surveillance pathway, triggered by endogenous or environmental danger or damage associated molecular patterns in a progressively expanding cascade of inflammation, tissue damage and cell death.

No MeSH data available.


Related in: MedlinePlus