form macromolecular complexes mediating gasdermin-d cleavage and induction of pyroptotic cell death. in addition, non-canonical inflammasomes may also indirectly activate the nlrp3 inflammasome by triggering potassium efflux through membrane pores formed by gasdermin-d. the nlrp3 inflammasome can then mediate processing of pro-inflammatory cytokines and result in release of il-1β and il-18 in response to non-canonical inflammasome activation. role in health role in innate immunity as part of the innate immune system, inflammasomes play an important role in the induction of inflammatory cascades and coordination of host defenses, both via the activation and secretion of pro-inflammatory cytokines and the induction of a specialized form of immune-stimulatory programmed cell death termed pyroptosis. inflammasomes and their components can also be involved in panoptosis, a unique form of inflammatory cell death that cannot be individually accounted for by pyroptosis, apoptosis, or necroptosis alone. in addition to professional cells of the innate immune system such as macrophages, several studies described various epithelial inflammasomes and highlighted their crucial role as a first line of defense. considering the importance of epithelia as common pathogen entry sites as a result of their location at the interface to the environment, it seems intuitive that epithelial tissues do not merely fulfill a function as a physical barrier, but additionally initiate a defensive response upon initial contact with the pathogen. in agreement with this, different inflammasome components were found to be expressed in a variety of epithelial tissues. expression of innate immune components at epithelial barriers furthermore facilitates pathogen detection given that expression of virulence factors and hence exposure of pamps is required for the breaching of these barriers during invasion, whereas these factors might be downregulated when the pathogen interacts with professional immune cells at later stages of infection. epithelial inflammasomes have mainly been studied in the intestinal mucosa, but there is also evidence for inflammasomes in other types of epithelial such as the urinary bladder epithelium. while the murine caspase-11 is mainly expressed in macrophages, human caspase-4 is also expressed at high levels in intestinal epithelial cells. similar to what was observed for the epithelial naip/nlrc4 inflammasome, human epithelial cells were shown to undergo caspase-4-dependent, caspase-1-independent cell death and extrusion in response to infection with the enteropathogens such as salmonella, shigella flexneri or escherichia coli. furthermore, secretion of il-18 could be triggered by cytosolic lps in epithelial cells. role of epithelial inflammasome 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 with other cell types on a local and global level. these downstream consequences of inflammasome activation can be divided into three categories, namely (1) death of the epithelial cell itself, (2) release of soluble pro-inflammatory molecules, and (3) effector cell recruitment and activation. in addition, epithelial inflammasome activation induces contraction of epithelial layers and prevents integrity loss at later stages of infection. in order to maintain the integrity of the epithelial barrier, cell death and subsequent extrusion of the infected cell have to occur in a coordinated manner to ensure sealing of the gap in the epithelium by neighboring cells. epithelial cell death can be triggered in a direct, cell-autonomous manner by inflammasome activation itself, as well as by local recruitment of other death-inducing cell types, or global inflammation, resulting in increased epithelial turnover that removes both infected and uninfected cells. the most important consequence of epithelial cell death is the reduction of epithelial pathogen loads in order to maintain barrier integrity. inflammasome activation is known to trigger cleavage, activation and secretion of pro-inflammatory il-1β and il-18, which then recruit different types of effector cells and coordinate the innate immune response. expression of pro-il-1β is dependent on toll-like-receptor signaling, and hence intestinal epithelial cells produce very low levels of il-1β themselves. pro-il-18, on the other hand, is constitutively expressed by different kinds of epithelial cells, and readily secreted upon inflammasome activation. the il-18 secreted by the epithelium can induce production of ifn-γ by different cell types. importantly, inflammasome-derived il-18 is also involved in recruitment of natural killer (nk) cells, that play a crucial role at early stages of innate immune responses. furthermore, il-18 can also stimulate the effector functions of nk cells that accumulated at the site of infection. the activated nk cells can then help in restricting the pathogen loads and spread to systemic sites at later time points compared to epithelium-autonomous induction of cell death. finally, nk cells also secrete ifn-γ in order to recruit other inflammatory cell types. in a study of upec infection of the urinary bladder epithelium, epithelial cells were found to secrete il-1β at high levels in response to bacterial infection. the study reported il-1β secretion to be dependent on the nlrp3 inflammasome and caspase-1, and the secreted pro-inflammatory cytokine was required for recruitment of mast cells to the site of infection. the mast cells then induce a lytic form of cell death in the epithelium by secreting granules that are taken up by the epithelium. besides nk cells and mast cells, 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 are involved in the recruitment of neutrophils. once they have reached the infected tissue, the neutrophils assist in immobilizing and eliminating the invading pathogens, whereby they either directly engulf or kill invading microbes. furthermore, they secrete inflammatory mediators such as ifn-γ and il-22. ifn-γ is known to drive activation of microbicidal capacity of mononuclear phagocytes. il-22, on the other hand, will strengthen the epithelial barrier. finally, neutrophils are responsible for the elimination of bacteria that are trapped within pyroptotic macrophages. role in disease problems with regulating inflammasomes have been linked to several autoimmune diseases such as type i and type ii diabetes, inflammatory bowel disease (ibd), gouty arthritis, multiple sclerosis, and vitiligo as well as auto-inflammatory disorders. gain-of-function mutations in inflammasome components are also known to cause cryopyrin-associated periodic syndrome (caps), a group of congenital diseases characterised by il-1β-mediated systemic inflammation. clinical significance there has been some progress in the development of nlrp3 inhibitors some include: dapansutrile, and diarylsulfonylurea mcc-950.