The pathogenic role of the inflammasome in neurodegenerative diseases

Freeman, Leslie; Ting, Jenny P.‐Y.

doi:10.1111/jnc.13217

Cited by 254 publications

(195 citation statements)

References 83 publications

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“…The triggering of inflammatory responses initiated by inflammasomes is emerging as a crucial component that contribute to neurodegenerative disorders (reviewed in [6] and [10]). Activation of inflammasome pathways is responsible for activation of inflammatory processes, and can induce cell pyroptosis, a process of programmed cell death distinct from apoptosis [51, 52].…”

Section: Discussionmentioning

confidence: 99%

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

et al. 2016

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Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with Valosin Containing Protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones and brain. In this report, we demonstrate: (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, Caspase 1, IL-1β and IL-18 in the quadriceps muscles of VCPR155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages that infiltrate the muscles of VCPR155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β (+)F4/80(+)Ly6C(+) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; (v) treatment of VCPR155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80(+)Ly6C(+)IL-1β (+) macrophage infiltrates in the muscle and significantly ameliorated muscle strength. Together, these results suggest: (i) NLRP3 inflammasome and local IL-1β (+)F4/80(+)Ly6C(+) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy; and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.

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Section: Discussionmentioning

confidence: 99%

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

et al. 2016

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“…Dysregulation of the inflammasome NLPR3 due to genetic mutations of its related genes has been implicated in other inflammatory diseases such as cryopyrinassociated periodic syndromes, familial Mediterranean fever, pyogenic arthritis, pyoderma gangrenosum, and acne syndrome 36 . Both the NLPR3 inflammasome and caspase-1 are also key players in the molecular mechanisms underlying other diseases in which inflammation plays a critical role in the pathophysiology, such as psoriasis, gout, and Alzheimer's disease 36,37 . Our data suggest that the genetic influences of NLPR3 inflammasome and caspase-1 merit further investigation in mediating the pathology and risk of Chagas disease as well.…”

Section: Discussionmentioning

confidence: 99%

Association of caspase-1 polymorphisms with Chagas cardiomyopathy among individuals in Santa Cruz, Bolivia

Zamudio

Henderson-Frost

et al. 2017

Rev. Soc. Bras. Med. Trop.

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Introduction: Trypanosoma cruzi (Tc) infection is usually acquired in childhood in endemic areas, leading to Chagas disease, which progresses to Chagas cardiomyopathy in 20-30% of infected individuals over decades. The pathogenesis of Chagas cardiomyopathy involves the host inflammatory response to T. cruzi, in which upstream caspase-1 activation prompts the cascade of inflammatory chemokines/cytokines, cardiac remodeling, and myocardial dysfunction. The aim of the present study was to examine the association of two caspase-1 single nucleotide polymorphisms (SNPs) with cardiomyopathy. Methods: We recruited infected (Tc+, n = 149) and uninfected (Tc−, n = 87) participants in a hospital in Santa Cruz, Bolivia. Cardiac status was classified (I, II, III, IV) based on Chagas cardiomyopathy-associated electrocardiogram findings and ejection fractions on echocardiogram. Genotypes were determined using Taqman probes via reverse transcription-polymerase chain reaction of peripheral blood DNA. Genotype frequencies were analyzed according to three inheritance patterns (dominant, recessive, additive) using logistic regression adjusted for age and sex. Results: The AA allele for the caspase-1 SNP rs501192 was more frequent in Tc+ cardiomyopathy (classes II, III, IV) patients compared to those with a normal cardiac status (class I) [odds ratio (OR) = −2.18, p = 0.117]. This trend approached statistical significant considering only Tc+ patients in class I and II (OR = −2.64, p = 0.064). Conclusions: Caspase-1 polymorphisms may play a role in Chagas cardiomyopathy development and could serve as markers to identify individuals at higher risk for priority treatment.

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“…In the human gut, AIM2 is predominantly expressed in macrophages and epithelial cells throughout the small and large intestine [16][17][18]. AIM2 is best known as an intracellular danger sensor present in a number of tissues with strong immune regulation other than the gut, such as the lungs [19][20][21], joints [22,23], skin [24,25], liver [26][27][28], brain [29,30] and gingiva [31,32]. Furthermore, AIM2 has been associated with (auto-)…”

Section: Absent In Melanomamentioning

confidence: 99%

Review Article. Absent in melanoma 2 (AIM2) in the intestine: diverging actions with converging consequences

Vanhove¹,

Peeters²,

Cleynen³

et al. 2017

Inflammasome

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epithelial cell proliferation, tight junction expression and the microbiome. Therefore, AIM2 plays a significant role in maintaining intestinal homeostasis. This review focuses on the multifunctional role of AIM2 in intestinal homeostasis by regulating intestinal immunity and preventing colorectal cancer development.Keywords: Inflammasome, Inflammatory Bowel Disease, Colorectal Cancer, Proliferation, Antimicrobial Peptides, Intestinal Microbiota, Tight Junctions 1 Introduction Inflammasomes in intestinal homeostasisRegulation of normal intestinal mucosal function is essential for the host's survival. The continuous interaction between the xenogenous and microbial environment, and the gut's immune system demands optimal regulation. Impaired functioning may result in intestinal barrier dysfunction, dysbiosis, inflammation and carcinogenesis [1,2]. Inflammasomes are important immune regulators for intestinal homeostasis that allow recruitment and activation of the inflammatory caspase-1, upon stimulation by a wide variety of triggers. This will activate downstream mediators, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), that, in combination with other alarm molecules (eg. high mobility group box 1, HMGB1) are the driving force of inflammation [3]. Furthermore, activated caspase-1 can also trigger pyroptosis, a specific form of cell death associated with inflammation. In contrast to apoptosis, pyroptosis will release cytoplasmic components into the extracellular space that can fuel inflammatory processes in adjacent cells [4][5][6]. This distinction is important as apoptosis is characterized by chromatin condensation, cell vacuolization and phagocytosis Abstract: The intestinal mucosa is a difficult environment to maintain homeostasis as it is constantly challenged by microbial and food antigens. Maintaining an intact epithelial barrier, a continuous turnover of intestinal epithelial cells and normobiosis of the gut microbiota are essential components to prevent intestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Inflammasomes are critical immune regulators that are involved in all of these processes. They are multiprotein complexes able to assemble upon interaction with a noxious stimulus that will subsequently lead to caspase-1 activation. Activated caspase-1 will orchestrate the maturation and release of proinflammatory cytokines IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. Both cytokine release and pyroptosis are initiated after detection of molecular patterns by a distinct inflammasome sensor protein. Absent in melanoma 2 (AIM2) is such an inflammasome sensor that specifically responds to the presence of double stranded DNA (dsDNA) in the cytoplasm, leading to the recruitment and activation of caspase-1. Recent studies revealed additional roles of AIM2 in controlling Review ArticleOpen Access

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The pathogenic role of the inflammasome in neurodegenerative diseases

Cited by 254 publications

References 83 publications

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Association of caspase-1 polymorphisms with Chagas cardiomyopathy among individuals in Santa Cruz, Bolivia

Review Article. Absent in melanoma 2 (AIM2) in the intestine: diverging actions with converging consequences

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