Inflammasomes and Colorectal Cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Keshavarz Shahbaz S
PROVIDER: S-EPMC8467678 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chronic inflammation plays a decisive role at different stages of cancer development. Inflammasomes are oligomeric protein complexes activated in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs and DAMPs are released from infected cells, tumors and damaged tissues. Inflammasomes activate and release inflammatory cytokines such as IL-1β and IL-18. The various inflammasomes and inflammatory cytokines and chemokines play contrasting roles in cancer development and progression. In this review, we describe the roles of different inflammasomes in lung, breast, gastric, liver, colon, and prostate cancers and in glioblastomas.
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Project description:The inflammasomes are critical regulators of innate immunity, inflammation and cell death and have emerged as important regulators of cancer development and control. Inflammasomes are assembled by pattern recognition receptors (PRR) following the sensing of microbial- or danger-associated molecular patterns (MAMPs/DAMPs) and elicit inflammation through the oligomerization and activation of inflammatory caspases. These cysteinyl-aspartate proteases cleave the proinflammatory cytokines IL-1β and IL-18 into their biologically active mature form. The roles of the inflammasomes and associated pro-inflammatory cytokines vary greatly depending on the cancer type. Here we discuss recent studies highlighting contrasting roles of the inflammasome pathway in curbing versus promoting tumorigenesis. On one hand, the inflammasomes participate in stimulating anti-tumor immunity, but they have also been shown to contribute to immunosuppression or to directly promote tumor cell survival, proliferation, and metastasis. A better understanding of inflammasome functions in different cancers is thus critical for the design of novel cancer immunotherapies.
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Project description:Inflammation-associated studies entice specific attention due to inflammation's role in multiple stages of prostate cancer development. However, mechanistic regulation of inflammation inciting prostate cancer remains largely uncharacterized. A focused class of inflammatory regulators known as inflammasomes has recently gained attention in cancer development. Inflammasomes are a multiprotein complex that drives a cascade of proinflammatory cytokines regulating various cellular activities. Inflammasomes activation is linked with infection, stress, or danger signals, which are common events within the prostate gland. In this study, we review the potential of inflammasomes in understanding the role of inflammation in prostate cancer.
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Project description:Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.
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Project description:The NOD-like receptor (NLR) family members are cytosolic sensors of microbial components and danger signals. A subset of NLRs control inflammasome assembly that results in caspase-1 activation and, in turn, IL-1? and IL-18 production. Excessive inflammasome activation can cause autoinflammatory disorders, including the hereditary periodic fevers. Autoinflammatory and autoimmune diseases form a disease spectrum of aberrant, immune-mediated inflammation against self, through innate and adaptive immunity. However, the role of inflammasomes in autoimmune disease is less clear than in autoinflammation, despite the numerous effects IL-1? and IL-18 can have on shaping adaptive immunity. We summarize the role of inflammasomes in autoimmune disorders, highlight the need for a better understanding of inflammasomes in these conditions and offer suggestions for future research directions.
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Project description:Fibrosis is the final common pathway of inflammatory diseases in various organs. The inflammasomes play an important role in the progression of fibrosis as innate immune receptors. There are four main members of the inflammasomes, such as NOD-like receptor protein 1 (NLRP1), NOD-like receptor protein 3 (NLRP3), NOD-like receptor C4 (NLRC4), and absent in melanoma 2 (AIM2), among which NLRP3 inflammasome is the most studied. NLRP3 inflammasome is typically composed of NLRP3, ASC and pro-caspase-1. The activation of inflammasome involves both "classical" and "non-classical" pathways and the former pathway is better understood. The "classical" activation pathway of inflammasome is that the backbone protein is activated by endogenous/exogenous stimulation, leading to inflammasome assembly. After the formation of "classic" inflammasome, pro-caspase-1 could self-activate. Caspase-1 cleaves cytokine precursors into mature cytokines, which are secreted extracellularly. At present, the "non-classical" activation pathway of inflammasome has not formed a unified model for activation process. This article reviews the role of NLRP1, NLRP3, NLRC4, AIM2 inflammasome, Caspase-1, IL-1β, IL-18 and IL-33 in the fibrogenesis.
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Project description:Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut-brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.
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Project description:Plasma cholesterol levels have been strongly associated with atherogenesis, underscoring the role of lipid metabolism in defining cardiovascular disease risk. However, atherosclerotic plaque is highly dynamic and contains elements of both the innate and adaptive immune system that respond to the aberrant accumulation of lipids in the subendothelial space. Previous research has focused on defining how proinflammatory cytokines synthesized by macrophages, such as interleukin-1? (IL-1?), modulate the progression of atherosclerosis, supporting the notion that chronic inflammation accelerates atherogenesis. More recently, emphasis has been placed on the elucidation of the mechanisms that contribute to pro-IL-1? production and finally its processing via multiprotein complexes termed the inflammasomes, a family of cytosolic multiprotein complexes that serve as sensors of either pathogen invasion or cellular stress (ie, cholesterol crystals) and work via triggering caspase-1-mediated processing of pro-IL-1? to IL-1?. Based on this link between cholesterol metabolism, NLRP3 inflammasome activation, and IL-1? release, it is important to re-evaluate how the atherogenic environment stimulates immune cells to produce IL-1?.
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Project description:Inflammasomes comprise a family of cytosolic multi-protein complexes that sense infection, or other threats, and initiate inflammation via the recruitment and activation of the Caspase-1 protease. Although the precise molecular mechanism by which most inflammasomes are activated remains a subject of considerable debate, the NAIP/NLRC4 subfamily of inflammasomes is increasingly well understood. A crystal structure of NLRC4 was recently reported, and a domain in NAIPs that recognizes bacterial ligands was identified. In addition, gain-of-function mutations in NLRC4 have been shown to cause an auto-inflammatory syndrome in humans. Lastly, the NAIP/NLRC4 inflammasome has been shown to provide a novel form of cell intrinsic defense against Salmonella infection, involving expulsion of infected cells from the intestinal epithelium.
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