NLRP3 Inflammasome Is a Target for Development of Broad-Spectrum Anti-Infective Drugs

Thacker, James D.; Balin, Brian J.; Appelt, Denah M.; Sassi-Gaha, Sihem; Purohit, Mitali; Rest, Richard F.; Artlett, Carol M.

doi:10.1128/aac.06372-11

Cited by 23 publications

(30 citation statements)

References 38 publications

(40 reference statements)

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“…In response to pathogens, inflammasomes are activated and can induce immune responses that restrict pathogen replication. Therefore, the inflammasome is a potential molecular target for developing novel anti-bacteria agents [29], [30]. In the current study, we show that UgU promotes the NLRP3 inflammasome-mediated innate immune response and enhances clearance of engulfed bacterial pathogens.…”

Section: Discussionsupporting

confidence: 52%

“…Thus, to the best of our knowledge, UgU is the first described natural flavonoid that activates human neutrophils and monocytes; both these cell types are expert microbial killers and are essential for the resolution of infections. Since the NLRP3 Inflammasome is a target for development of anti-infective medicines [29], [30], [60], we expect that further investigation of UgU will facilitate the development of novel anti-infective agents. Studies of UgU will also enhance our understanding of the pharmacology of flavonoids.…”

Section: Discussionmentioning

confidence: 99%

“…This has stimulated research aimed at identifying chemical agents or natural products that can activate the complex and therefore modulate innate immunity and host defense [27], [28], [29], [30]. We previously reported that ugonin U (UgU, 4′′a,5′′,6′′,7′′,8′′,8′′a-hexahydro-5,3′,4′-trihydroxy-5′′,5′′,8′′a-trimethyl-4H-chromeno [2′′,3′′:7,6]flavone, Fig.…”

Section: Introductionmentioning

confidence: 99%

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Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

et al. 2017

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The NOD-like receptor pyrin domain 3 (NLRP3) inflammasome contains Nod-like receptors, a subclass of pattern recognition receptors, suggesting that this complex has a prominent role in host defenses. Various structurally diverse stimulators activate the NLRP3 inflammasome through different signaling pathways. We previously reported that ugonin U (UgU), a natural flavonoid isolated from Helminthostachys zeylanica (L) Hook, directly stimulates phospholipase C (PLC) and triggers superoxide release in human neutrophils. In the present study, we showed that UgU induced NLRP3 inflammasome assembly and subsequent caspase-1 and interleukin (IL)-1β processing in lipopolysaccharide-primed human monocytes. Moreover, UgU elicited mitochondrial superoxide generation in a dose-dependent manner, and a specific scavenger of mitochondrial reactive oxygen species (ROS) diminished UgU-induced IL-1β and caspase-1 activation. UgU induced Ca2+ mobilization, which was inhibited by treatment with inhibitors of PLC or inositol triphosphate receptor (IP3R). Blocking Ca2+ mobilization, PLC, or IP3R diminished UgU-induced IL-1β release, caspase-1 activation, and mitochondrial ROS generation. These data demonstrated that UgU activated the NLPR3 inflammasome activation through Ca2+ mobilization and the production of mitochondrial ROS. We also demonstrated that UgU-dependent NLRP3 inflammasome activation enhanced the bactericidal function of human monocytes. The ability of UgU to stimulate human neutrophils and monocytes, both of which are professional phagocytes, and its capacity to activate the NLRP3 inflammasome, which is a promising molecular target for developing anti-infective medicine, indicate that UgU treatment should be considered as a possible novel therapy for treating infectious diseases.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

et al. 2017

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“…RNA:DNA hybrids of enterohemorrhagic E. coli were shown to activate the NLRP3 inflammasome, a finding that provided new insights into cytosolic immune surveillance mechanisms (21). The NLRP3 inflammasome may be a suitable target for new drugs to treat infectious diseases, including mastitis, in a manner that avoids the risk of antibiotic resistance development (22).…”

mentioning

confidence: 99%

Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Inflammation and Cell Damage via Attenuation of ASC-Independent NLRP3 Inflammasome Activation

Liu

Yang

et al. 2016

Appl Environ Microbiol

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Escherichia coli is a major environmental pathogen causing bovine mastitis, which leads to mammary tissue damage and cell death. We explored the effects of the probiotic Lactobacillus rhamnosus GR-1 on ameliorating E. coli-induced inflammation and cell damage in primary bovine mammary epithelial cells (BMECs). Increased Toll-like receptor 4 (TLR4), NOD1, and NOD2 mRNA expression was observed following E. coli challenge, but this increase was attenuated by L. rhamnosus GR-1 pretreatment. Immunofluorescence and Western blot analyses revealed that L. rhamnosus GR-1 pretreatment decreased the E. coli-induced increases in the expression of the NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3) and the serine protease caspase 1. However, expression of the adaptor protein apoptosis-associated speck-like protein (ASC, encoded by the Pycard gene) was decreased during E. coli infection, even with L. rhamnosus GR-1 pretreatment. Pretreatment with L. rhamnosus GR-1 counteracted the E. coli-induced increases in interleukin-1␤ (IL-1␤), -6, -8, and -18 and tumor necrosis factor alpha mRNA expression but upregulated IL-10 mRNA expression. Our data indicate that L. rhamnosus GR-1 reduces the adhesion of E. coli to BMECs, subsequently ameliorating E. coli-induced disruption of cellular morphology and ultrastructure and limiting detrimental inflammatory responses, partly via promoting TLR2 and NOD1 synergism and attenuating ASC-independent NLRP3 inflammasome activation. Although the residual pathogenic activity of L. rhamnosus, the dosage regimen, and the means of probiotic supplementation in cattle remain undefined, our data enhance our understanding of the mechanism of action of this candidate probiotic, allowing for development of specific probiotic-based therapies and strategies for preventing pathogenic infection of the bovine mammary gland. Mastitis affects cows in all regions of the world and can cause a decrease in milk production and quality, resulting in a major economic burden to the dairy industry (1). Escherichia coli is by far the most common cause of mastitis, since it is isolated in more than 80% of cases of coliform mastitis (2). Antibiotic therapy frequently leaves residues in milk, potentially facilitating the development of antibiotic resistance. Probiotics represent a novel alternative to antibiotics for controlling pathogen infections.Lactobacillus rhamnosus GR-1 is a probiotic bacterium isolated from the female urethra, and oral ingestion of L. rhamnosus GR-1 and L. fermentum RC-14 reduces vaginal colonization by pathogenic bacteria and yeasts and maintains urogenital health in women (3). Pretreatment of pregnant CD-1 mice with L. rhamnosus GR-1 culture supernatant decreases lipopolysaccharide (LPS)-induced production of various cytokines and chemokines (4). Lactobacillus rhamnosus GR-1 suppresses expression of nuclear factor (NF)-B-related inflammatory genes and activates alternate mitogen-activated protein kinase (MAPK) and activator protein 1 pathways to recruit host defense factors...

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“…Both compounds selectively inhibit NLRP3 activity in macrophages in vitro, independent of their inhibitory effect on NF-kappaB activity. In contrast, TherimuneX Pharmaceuticals has produced a NLRP3 inflammasome activator, an acetylated 18-mer peptide (acALY18) that is used to enhance inflammasome-mediated pathogen clearance and that is beneficial as a broad-spectrum antiinfective drug (Thacker et al, 2012). The actual limitation in the discovery of drugs targeting the inflammasome is the complexity of the activation pathway.…”

Section: Discussionmentioning

confidence: 91%

Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies

Rimessi

Previati

Nigro

et al. 2016

The International Journal of Biochemistry & Cell Biology

157

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Over the last few decades, many different groups have been engaged in studies of new roles for mitochondria, particularly the coupling of alterations in the redox pathway with the inflammatory responses involved in different diseases, including Alzheimer's disease, Parkinson's disease, atherosclerosis, cerebral cavernous malformations, cystic fibrosis and cancer. Mitochondrial dysfunction is important in these pathological conditions, suggesting a pivotal role for mitochondria in the coordination of pro-inflammatory signaling from the cytosol and signaling from other subcellular organelles. In this regard, mitochondrial reactive oxygen species are emerging as perfect liaisons that can trigger the assembly and successive activation of large caspase-1- activating complexes known as inflammasomes. This review offers a glimpse into the mechanisms by which inflammasomes are activated by mitochondrial mechanisms, including reactive oxygen species production and mitochondrial Ca uptake, and the roles they can play in several inflammatory pathologies.

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NLRP3 Inflammasome Is a Target for Development of Broad-Spectrum Anti-Infective Drugs

Cited by 23 publications

References 38 publications

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

Ugonin U stimulates NLRP3 inflammasome activation and enhances inflammasome-mediated pathogen clearance

Lactobacillus rhamnosus GR-1 Ameliorates Escherichia coli-Induced Inflammation and Cell Damage via Attenuation of ASC-Independent NLRP3 Inflammasome Activation

Mitochondrial reactive oxygen species and inflammation: Molecular mechanisms, diseases and promising therapies

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