The cytosolic DNA sensor AIM2 promotes Helicobacter‐induced gastric pathology via the inflammasome

Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H. pylori–induced gastric...

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Vydáno v:Immunology and cell biology Ročník 101; číslo 5; s. 444 - 457
Hlavní autoři: Dawson, Ruby E, Deswaerte, Virginie, West, Alison C, Sun, Ekimei, Wray‐McCann, Georgie, Livis, Thaleia, Kumar, Beena, Rodriguez, Emiliana, Gabay, Cem, Ferrero, Richard L, Jenkins, Brendan J
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Blackwell Science Ltd 01.05.2023
John Wiley and Sons Inc
Témata:
Absent in melanoma 2 (AIM2)
Animals
Apoptosis
Biopsy
Caspase
Cell proliferation
Chemokines
Chronic infection
Cytokines
Cytokines - metabolism
Disease
DNA-Binding Proteins - metabolism
Felis - metabolism
Gastric cancer
Gastric Mucosa - metabolism
Gastric Mucosa - pathology
gastritis
Gene expression
Helicobacter
Helicobacter - metabolism
Humans
Hyperplasia
Immune response
inflammasome
Inflammasomes
Inflammasomes - metabolism
Inflammation - pathology
Inflammatory diseases
Innate immunity
Melanoma
Mice
Mucosal immunity
Original
Pathogenesis
Pathology
Precancerous Conditions - pathology
Stomach Neoplasms
Helicobacter
gastritis
inflammasome
Absent in melanoma 2 (AIM2)
ISSN:0818-9641, 1440-1711, 1440-1711
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Shrnutí:Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H. pylori–induced gastric pathology remain ill‐defined. The innate immune cytosolic DNA sensor absent in melanoma 2 (AIM2) contributes to the pathogenesis of numerous autoimmune and chronic inflammatory diseases, as well as cancers including gastric cancer. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter‐induced gastric disease. Here, we reveal that AIM2 messenger RNA and protein expression levels are elevated in H. pylori–positive versus H. pylori–negative human gastric biopsies. Similarly, chronic Helicobacter felis infection in wild‐type mice augmented Aim2 gene expression levels compared with uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis–infected Aim2−/− versus wild‐type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and proinflammatory cytokine and chemokine release. In addition, H. felis–driven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2−/− stomachs. These observations in Aim2−/− mouse stomachs correlated with decreased levels of inflammasome activity (caspase‐1 cleavage) and the mature inflammasome effector cytokine, interleukin‐1β. Taken together, this work uncovers a pathogenic role for the AIM2 inflammasome in Helicobacter‐induced gastric disease, and furthers our understanding of the host immune response to a common pathogen and the complex and varying roles of AIM2 at different stages of cancerous and precancerous gastric disease. Helicobacter pylori infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system which leads to a cascade of precancerous lesions, culminating in gastric cancer. Here, we report that the innate immune DNA sensor absent in melanoma 2 (AIM2) promotes Helicobacter‐driven early gastric inflammation via the inflammasome, specifically through regulation of apoptosis and proliferation of gastric epithelial and immune cells.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0818-9641
1440-1711
1440-1711
DOI:10.1111/imcb.12641