Inflammasomes of the intestinal epithelium

Sellin, Mikael E.; Maslowski, Kendle M.; Maloy, Kevin J.; Hardt, Wolf‐Dietrich

doi:10.1016/j.it.2015.06.002

Cited by 80 publications

(74 citation statements)

References 83 publications

(169 reference statements)

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“…In contrast to the canonical inflammasome, caspase-11/4/5 mediated non-canonical inflammasome is activated by the cytosolic LPS, however, whether caspase-11/4/5 can directly cleave IL-1β or IL-18 remains controversial [41–42]. Given that the actions of inflammasomes have been well-studied in myeloid cells, accumulating evidence highlights their role in non-professional immune cells as an important antibacterial defense mechanism [43]. Recent studies demonstrated that epithelium utilize both canonical and non-canonical inflammasomes to promote mucosal defense against enteric bacterial pathogens [40–42].…”

Section: Discussionmentioning

confidence: 99%

Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

et al. 2018

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Inflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling remains undiscovered. Here, we show that hemolysin-overexpressed enterobacteria triggered significantly increased caspase-4 activation in human intestinal epithelial cell lines. Hemolysin promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin promoted caspase-11 dependent IL-18 secretion and gut inflammation in mice, which was associated with restricting bacterial colonization in vivo. Together, our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses.

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Section: Discussionmentioning

confidence: 99%

Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

et al. 2018

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“…Apart from NLRP3, NAIP/NLRC4 is also crucial in maintenance of the integrity of intestinal epithelium (170). NAIP/NLRC4 can respond to Gram-negative bacteria such as Salmonella Typhimurium and Citrobacter rodentium as well as bacterial components like type III secretion system (TTSS) and flagella (171–173).…”

Section: Transformation Between Inflammation and Cancers: Relevant DImentioning

confidence: 99%

“…The exposure to acute carcinogens can also be sensed. Intestinal epithelial cells will activate NAIP–NLRC4–caspase-1 axis which increases the secretion of IL-18 to activate protective gut immune responses (170). …”

Section: Transformation Between Inflammation and Cancers: Relevant DImentioning

confidence: 99%

Inflammasomes in Inflammation-Induced Cancer

Lin

Zhang

2017

Front. Immunol.

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The inflammasome is an important multiprotein complex that functions during inflammatory immune responses. The activation of inflammasome will lead to the autoactivation of caspase-1 and subsequent cleavage of proIL-1β and proIL-18, which are key sources of inflammatory manifestations. Recently, the roles of inflammasomes in cancers have been extensively explored, especially in inflammation-induced cancers. In different and specific contexts, inflammasomes exhibit distinct and even contrasting effects in cancer development. In some cases, inflammasomes initiate carcinogenesis through the extrinsic pathway and maintain the malignant cancer microenvironment through the intrinsic pathway. On the contrary, inflammasomes also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions. The phases and compartments in which inflammasomes are activated strongly influence the final immune effects. We systemically summarize the functions of inflammasomes in inflammation-induced cancers, especially in gastrointestinal and skin cancers. Besides, information about the current therapeutic use of inflammasome-related products and potential future developing directions are also introduced.

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“…IL-18 both promotes (facilitates tumor escape and angiogenesis) oncogenesis and suppresses (induces tumor cell death) oncogenesis [11][12][13][14]. IL-18 activates endothelial cell migration and increases angiogenesis in vivo [12].…”

Section: Role Of Il-18 In Colorectal Cancermentioning

confidence: 99%

“…NLRP1 plays a protective role during experimental colitis and colitis-associated tumorgenesis in the mouse [8,13]. NLRP12 has a role in preventing chemically induced colitis and colon tumor associated with inflammation and serves as, a checkpoint protein by negatively regulating the non-canonical NF-kappa B signaling [3,20].…”

Section: Role Of Il-18 In Colorectal Cancermentioning

confidence: 99%

Colorectal Cancer and NLRP-Current Knowledge

J¹

2018

Immunome Res

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Inflammasomes activated by different stimuli in colorectal cancer show dual effect on cancer's destiny. Activation of caspase-1 results in maturation of IL-1β and IL-18. IL-1β suppresses NK and T cells activity against tumor, induces expression of metastatic genes and stimulates the production of proinflammatory leukines, but it also enhances NK cell-mediated death of colon carcinoma cells. IL-18 promoter polymorphisms in humans increase risk for colorectal cancers.One variant of NLRP3 gene in human is connected with increased susceptibility to colorectal cancer. Expression levels of NLRP1, NLRP3, NLRC4 were significantly reduced in human CRC compared with healthy controls. Nlrp3 −/−mice exhibited increased colorectal cancer and metastasis in liver.NLRP3 have an important role in the Epithelial-Mesenchymal Transition (EMT) of colorectal cancer cells, which is necessary for migration and invasion. Absence of NLRP3 in colorectal carcinoma cells diminishes tumor cells migration and invasion.

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Inflammasomes of the intestinal epithelium

Cited by 80 publications

References 83 publications

Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

Dysregulated hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing

Inflammasomes in Inflammation-Induced Cancer

Colorectal Cancer and NLRP-Current Knowledge

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