Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses.
Protein complexes referred to as inflammasomes, part of the innate immune system that helps regulate inflammation, appear to be an important contributor to the development of obesity-related colon cancer, if not other cancers.
The inflammasome is a multi-protein complex consisting of a sensor, an adapter, and an effector, that when activated, modulates caspases which cleave cytokines and result in an inflammatory signaling response.
Receptors present on the cell surface act as sensors for the detection of damage and pathogens.
When activated, this system can go on to elicit pro-inflammatory cytokine secretion and sometimes cell death.
Pro-inflammatory cytokines secretion acts as the effector or the response to such stimuli.
Stimuli that can fuel inflammasome assembly include pathogen-associated molecular patterns (PAMPS), damage associated molecular patterns (DAMPS), and nutrients.
Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18).
The term inflammasome describes the multiprotein complex needed for caspase-1 processing and activation of the inflammatory cytokines such interleukin-1β (IL-1β) and IL-18.
The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane.
Inflammasome is an intracellular multiprotein complex assembled by NOD-like receptors (NLRs) and DNA sensors.
When there is dysregulation of inflammasome activation, major diseases, such as cancer, autoimmune, metabolic and neurodegenerative diseases may arise.
Inflammasomes exist in the immune cells of the innate immune system, such as macrophages.
There are high levels of inflammasome expression in epithelial barrier tissues, where they are an important first line of defense.
Inflammasomes are multiprotein signals responsible for the maturation of pro-IL-1β and pro-IL-18 as well as the induction of an inflammatory cell death termed pyroptosis.
Inflammasome activation is initiated by pathogen-associated molecular patterns or danger-associated molecular patterns generated by the host cell.
It can be triggered by series of signals evoked by the presence of pathogens and cellular stress.
Danger signals could provoke a response from an inflammasome including viral DNA, asbestos, and silica.
One of the first forms of defense of an infection is by the innate immune response by a group of pattern recognition receptors (PRRs) to recognize molecular patterns expressed by invading pathogens.
Inflammasomes as part of the innate immune system, play an important role in the induction of inflammatory cascades and coordination of host defenses.
Inflammasomes activate and secrete pro-inflammatory cytokines and the induction of a form of immune-stimulatory programmed cell death termed pyroptosis.
There are inflammasomes in epithelial cells in important barrier tissues such as the intestines, positioned to recognize invading microbes at the first point of interaction.
Abnormal activation of the inflammasomes is a risk factor for the emergence of autoimmune, autoinflammatory, chronic inflammatory, and metabolic diseases.
The inflammasome activates a pyroptotic inflammatory cascade.
The inflammasome is a detector of cytosolic double stranded DNA (dsDNA) and plays an important role in the coordination of immune defense to DNA virus infections, as well as intracellular bacterial infections.
AIM2 inflammasone is activated by viral dsDNA, bacterial dsDNA and aberrant host dsDNA, and is linked to different human diseases.
Autoinflammation in psoriasis was found to be connected to recognition of self-DNA by AIM2.
Activation of the AIM2 plays a role in autoimmune responses to systematic lupus erythematosus.
The AIM2 inflammasome is also activated by pharmacological disruption of nuclear envelope integrity.
Inflammasome-mediated defense was found to play a crucial role as a first line of defense against bacteria at epithelial sites.
Inflammasome components are found to be expressed in a variety of epithelial tissues.
There is also evidence for inflammasomes in other types of epithelial such as the urinary bladder epithelium.
Intracellular bacteria trigger activation of the inflammasome, which results in specific expulsion of infected epithelial cells from the epithelium in order to reduce the bacterial load.
Human caspase-4 is also expressed at high levels in intestinal epithelial cells.
Epithelial cells undergo caspase-4-dependent cell death and extrusion in response to infection with the enteropathogens such as Salmonella, Shigella flexneri or Escherichia coli.
Activation of epithelial inflammasomes in response to invading pathogens has important cell-autonomous effects on the infected cell itself as well as on its communication.
These downstream consequences of inflammasome activation can be divided into three categories, namely (1) death of the epithelial cell itself, (2) release of pro-inflammatory molecules, and (3) effector cell recruitment and activation.
Following cell death and its extrusion from the epithelial barrier, timely sealing of the gap in the epithelium by neighboring cells occurs.
Epithelial cell death results the reduction of epithelial pathogen loads in order to maintain barrier integrity.
Inflammasome activation promotes, secretion of pro-inflammatory IL-1β and IL-18, which then recruit different types of effector cells and coordinate the innate immune response.
Pro-IL-18, is constitutively expressed by epithelial cells, and readily secreted upon inflammasome activation.
The IL-18 secreted by the epithelium can induce production of IFN-γ.
Inflammasome-derived IL-18 is involved in recruitment of natural killer (NK) cells, that play a crucial role at early stages of innate immune responses.
IL-18 can also stimulate the effector functions of NK cells that accumulated at the site of infection.
NK cells also secrete IFN-γ in order to recruit other inflammatory cell types.
NK cells, mast cells, and neutrophils are other important innate immune effector cells that infiltrate the infected tissue after breaching of epithelial barriers by pathogens.
Both IL-1β and IL-18 secreted in response to inflammasome activation and help in the recruitment of neutrophils.
Neutrophils assist in immobilizing and eliminating the invading pathogens, engulfing or kill invading microbes.
Neutrophils secrete inflammatory mediators such as IFN-γ and IL-22.
IFN-γ drives activation of microbicidal capacity of mononuclear phagocytes.
IL-22 strengthens the epithelial barrier.
Neutrophils are responsible for the elimination of bacteria that are trapped within macrophages.
Dysregulation of the inflammasome has been linked to several autoimmune diseases such as type I and type II diabetes, inflammatory bowel disease (IBD), gouty arthritis, multiple sclerosis, vitiligo, and auto-inflammatory disorders.
Colchicine has also been associated with disrupting inflammasome activation, thereby suppressing caspase-1 activation and the subsequent release of IL-1β and IL-18.
Such diseases/disorders are connected to too much or too little release of the pro-inflammatory cytokines that the inflammasome is responsible for.
Mutations in the adaptive immune system may be to blame for the dysregulation of the inflammasome.
Most inflammasomes consist of an upstream sensor, an adaptor protein and inflammatory caspases such as caspase-1.
Inflammasomes play a role in the pathogenesis of liver disease, inflammasome components are expressed by various cell types in the liver such as Kupffer cells and sinusoidal endothelial cells.
Inflammasome activation is mediated by the immune system.
The inflammasome complex is implicated in regulating the secretion of nonconventional alarm molecules, lipid biogenesis, glycolysis, and inflammation-induced cell death with characteristics of apoptosis and necrosis called pyroptosis.
Activation of the inflammasomes should be controlled to avoid unwanted host damage and too much inflammation.
Maturation of IL-1β and IL-18 by cleavage with caspase-1 is necessary to provoke the immune response.
The recognition component of the inflammasome is the receptor protein.
The inflammasome formation leads to the autocleavage and activation of caspase-1.
The activated caspase-1 triggers the processing and release of proinflammatory cytokines interleukin-1 beta and interleukin-18, which are important for the shaping of adaptive immune responses.
Caspase-1 activation triggers a form of cell death termed pyroptosis, and the release of interleukin-1 beta is a hallmark of inflammasome activation.
Inflammasomes are important multiprotein complexes that are activated by a variety of pathways that cleave and release mature pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-18 (IL-18).
Activation of the inflammasome serves in a regulatory capacity in the induction of pyroptotic cell death to remove the damaged immune cells.
NLRP3 inflammasome could be crucial in ensuring maintenance of a fully functioning population of microglia.
Inflammasomes have been implicated in the metabolic syndrome and in the cause of type 2 diabetes.
NLRP3 inflammasome and caspase 1 effect adipocyte differentiation and insulin sensitivity through IL-1β.
Caloric restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes are associated with reduced NLRP3 inflammasome expression in adipocytes as well as with decreased inflammation and improved insulin sensitivity.
Obesity-associated
signals and metabolites might potentially activate the inflammasome.
Saturated fatty acids, reactive oxygen species, and ceramide stimulate caspase 1 catalysis in macrophages and adipose tissue.
Hyperglycemia activates the inflammasome.
It is suggested the inflammasome regulates glucose metabolism under stress conditions and mediates the low-level chronic inflammation associated with obesity and diabetes.
Inflammasomes are an important component of the macrophage response to a variety of stimuli, including free fatty acids, DNA, and uric acid crystals, among others.
The inflammasome, is responsible for caspase-1 activation, the intracellular cysteine proteases that cleave substrates after aspartate residues and play integral roles in apoptosis
Caspases are classified as proinflammatory or proapoptotic, depending upon the cellular processes in which they are involved.
The proinflammatory caspases include caspases 1, 4, and 5 in humans.
Caspase-1, also known as ICE (interleukin-1 beta converting enzyme), is responsible for the cleavage of prointerleukin-1, -18, and -33 into their mature forms, IL-1β, IL-18, and IL-33.
Acetaminophen toxicity is related to hepatocyte DNA activation by inflammasomes.
The inflammasome is key in the regulation of cellular stress and immune responses.
Inflammasomes as multiprotein complexes regulate the processing and secretion of proinflammatory cytokines.
Iinflammasome formation regulates mucus secretion by goblet cells.
The NLR family member NLRP6 is an important regulator of inflammasome formation in the intestine.
Genetic deletion of NLRP6 results in reduced intestinal IL-18 production,altered microbiota, spontaneous intestinal hyperplasia, inflammatory cell recruitment, and enhanced susceptibility to chemically induced colitis.
NLRP6-dependent inflammasomes regulate mucus secretion by goblet cells.
There is a connection among inflammasome activation, autophagy, and mucus production by the colon epithelium.
Population-based studies have shown that individuals who are prone to develop chronic inflammatory diseases are at increased risk of cancer, and inflammasomes play an important role in cancer development showing tumor-promoting or tumor-suppressive actions depending on the type of tumor, the specific inflammasome involved, and downstream effector molecules.
In obesity and colon cancer there is an increased gene expression levels of the proteins NLRP3, NLRP6, ASC, and NOD2 in visceral adipose tissue.
This suggests that obesity-associated visceral adipose tissue inflammation creates a microenvironment favorable for colon cancer development.
Blocking the expression of NLRP3 reduces visceral adipose tissue inflammation and significantly attenuates fibrosis that contributes to the development of obesity-associated comorbidities including type 2 diabetes and nonalcoholic fatty liver disease.
NLRP6 is an important factor in the intestinal injury response which regulates aspects of healing inflammation, and is also linked to epithelial integrity and the loss of NLRP6, and IL-18 – its main effector in the intestine has been associated with increased mortality in colorectal cancer.
Reduced expression of NLRP6 and IL-18 in the colon from patients with colon cancer suggests an impaired regulation in the inflammatory cascade and a decrease in the integrity of the intestinal barrier.
Gene expression levels of adiponectin, an anti-inflammatory protein produced by adipose tissue, are reduced in visceral adipose tissue in individuals who were obese as well as those with colon cancer.
Low levels of adiponectin have, in turn, been linked to a higher risk of colorectal cancer.
Normal levels of adiponectin inhibit colorectal cancer cell growth.