The Role of NLRP3 and IL-1β in the Pathogenesis of Inflammatory Bowel Disease

Mao, Liming; Kitani, Atsushi; Strober, Warren; Fuss, Ivan J.

doi:10.3389/fimmu.2018.02566

Cited by 189 publications

(138 citation statements)

References 47 publications

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“…Together, these studies highlight the complexity of NLRP3 inflammasome responses and downstream mediators in Crohn's disease, and indicate important potential avenues of investigation that examine the effects of gain‐ and loss‐of‐function mutations in NLRP3 that can result in hyperproduction and hypoproduction of IL‐1 family cytokines, respectively (reviewed in Refs. 51 and 52 ). These data support a rationale for assessing dysfunctional NLRP3 inflammasome‐driven responses in IBDs.…”

Section: Nlrp3 Inflammasomes In the Gutmentioning

confidence: 98%

The role of the microbiome and the NLRP3 inflammasome in the gut and lung

Donovan

Liu

Shen

et al. 2020

Journal of Leukocyte Biology

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The nucleotide‐binding oligomerization domain (NOD)‐like receptor (NLR) family, pyrin domain‐containing protein 3 (NLRP3) inflammasome, is one of the most well‐characterized inflammasomes, activated by pathogen‐associated molecular patterns and damage‐associated molecular patterns, including from commensal or pathogenic bacterial and viral infections. The NLRP3 inflammasome promotes inflammatory cell recruitment and regulates immune responses in tissues such as the gastrointestinal tract and the lung, and is involved in many diseases that affect the gut and lung. Recently, the microbiome in the gut and the lung, and the crosstalk between these organs (gut–lung axis), has been identified as a potential mechanism that may influence disease in a bidirectional manner. In this review, we focus on themes presented in this area at the 2019 World Congress on Inflammation. We discuss recent evidence on how the microbiome can affect NLRP3 inflammasome responses in the gut and lung, the role of this inflammasome in regulating gut and lung inflammation in disease, and its potential role in the gut–lung axis. We highlight the exponential increase in our understanding of the NLRP3 inflammasome due to the synthesis of the NLRP3 inflammasome inhibitor, MCC950, and propose future studies that may further elucidate the roles of the NLRP3 inflammasome in gut and lung diseases.

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Section: Nlrp3 Inflammasomes In the Gutmentioning

confidence: 98%

The role of the microbiome and the NLRP3 inflammasome in the gut and lung

Donovan

Liu

Shen

et al. 2020

Journal of Leukocyte Biology

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“…Increased expression of NLRP3 and secretion of IL-1β. Downregulation of NLRP6, NLRP12 (Mao et al, 2018) Rheumatoid arthritis Both (arterial and venous types). Due to endothelial injury and hypercoagubility.…”

Section: Inflammatory Bowel Diseasementioning

confidence: 99%

Understanding Inflammatory Responses in the Manifestation of Prothrombotic Phenotypes

Chanchal

Mishra

Singh

et al. 2020

Front. Cell Dev. Biol.

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Inflammasome complex is a multimeric protein comprising of upstream sensor protein of nucleotide-binding oligomerization domain (NOD)-like receptor family. It has an adaptor protein apoptosis-associated speck-like protein and downstream effector cysteine protease procaspase-1. Activation of inflammasome complex is body's innate response to pathogen attack but its abnormal activation results in many inflammatory and cardiovascular disorders including thrombosis. It has displayed a prominent role in the clot formation advocating an interplay between inflammation and coagulation cascades. Therefore, elucidation of inflammasome and its molecular mechanisms in the manifestation of prothrombotic phenotypes becomes pertinent. Thrombosis is the formation and propagation of blood clot in the arterial or venous system due to several interactions of vascular and immune factors. It is a prevalent pathology underlying disorders like venous thromboembolism, stroke and acute coronary syndrome; thus, making thrombosis, a major contributor to the global disease burden. Recently studies have established a strong connection of inflammatory processes with this blood coagulation disorder. The hemostatic balance in thrombosis gets altered by the inflammatory mechanisms resulting in endothelial and platelet activation that subsequently increases secretion of several prothrombotic and antifibrinolytic factors. The upregulation of these factors is the critical event in the pathogenesis of thrombosis. Among various inflammasome, nucleotide-binding domain, leucine-richcontaining family, pyrin domain containing 3 (NLRP3) is one of the best-studied sterile inflammasome strengthening a link between inflammation and coagulation in thrombosis. NLRP3 activation results in the catalytic conversion of procaspase-1 to active caspase-1, which facilitate the maturation of interleukin-1β (IL-1β) and interleukin-18. These cytokines are responsible for immune cells activation critical for immune responses. These responses further results in endothelial and platelet activation and aggregation. However, the exact molecular mechanism related to the pathogenesis of thrombosis is still elusive. There have been several reports that demonstrate Tissue factor (TF)-mediated signaling in the production of pro-inflammatory cytokines enhancing inflammation by activating protease-activated receptors on various cells,

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“…19 Dysregulated NLRP3 inflammasome activation is involved in diverse diseases, including neurodegenerative diseases, 20,21 osteoarthritis, 22 cancer, 23,24 and inflammatory diseases. 25,26 Few studies have investigated the relationship between NLRP3 inflammasome activation and IVDD. However, numerous studies have confirmed that IL-1β is an important cause of IVDD, 16,27 and so we hypothesized that the NLRP3 inflammasome activation/IL-1β inflammatory response axis may play an important role in IVDD progression and that eliminating stimuli that activate the NLRP3 inflammasome may alleviate this progression.…”

Section: Introductionmentioning

confidence: 99%

Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop

et al. 2020

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The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin (IL)-1β, and is one of the main causes of intervertebral disc degeneration (IVDD). NLR pyrin domain containing 3 (NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model; moreover, NLRP3 inflammasome activation (NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus (NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species (mtROS) production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mtROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.

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The Role of NLRP3 and IL-1β in the Pathogenesis of Inflammatory Bowel Disease

Cited by 189 publications

References 47 publications

The role of the microbiome and the NLRP3 inflammasome in the gut and lung

The role of the microbiome and the NLRP3 inflammasome in the gut and lung

Understanding Inflammatory Responses in the Manifestation of Prothrombotic Phenotypes

Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop

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