Fusobacterium nucleatuminfection of gingival epithelial cells leads to NLRP3 inflammasome-dependent secretion of IL-1β and the danger signals ASC and HMGB1

Abstract

Summary Fusobacterium nucleatum is an invasive anaerobic bacterium that is associated with periodontal disease. Previous studies have focused on virulence factors produced by F. nucleatum, but early recognition of the pathogen by the immune system remains poorly understood. Although an inflammasome in gingival epithelial cells (GECs) can be stimulated by danger-associated molecular patterns (DAMPs) (also known as danger signals) such as ATP, inflammasome activation by this periodontal pathogen has yet to be described in these cells. This study therefore examines the effects of F. nucleatum infection on pro-inflammatory cytokine expression and inflammasome activation in GECs. Our results indicate that infection induces translocation of NF-κB into the nucleus, resulting in cytokine gene expression. In addition, infection activates the NLRP3 inflammasome, which in turn activates caspase-1 and stimulates secretion of mature IL-1β. Unlike other pathogens studied until now, F. nucleatum activates the inflammasome in GECs in the absence of exogenous DAMPs such as ATP. Finally, infection promotes release of other DAMPs that mediate inflammation, such as high-mobility group box 1 protein and apoptosis-associated speck-like protein, with a similar time-course as caspase-1 activation. Thus, F. nucleatum expresses the pathogen-associated molecular patterns necessary to activate NF-κB and also provides an endogenous DAMP to stimulate the inflammasome and further amplify inflammation through secretion of secondary DAMPs.

Microbial characterization of esophageal squamous cell carcinoma and gastric cardia adenocarcinoma from a high‐risk region of China

“…NLRP3 inflammasome activation activates caspase 1 and induces secretion of mature IL‐1β. Also, an F. nucleatum infection can induce other damage‐associated molecular patterns that mediate inflammasomes, including high‐mobility group box 1 protein (HMGB1) and apoptosis‐associated speck‐like protein (ASP), with a time course similar to that of caspase 1 activation . Studies have found that P. gingivalis is detected frequently in esophageal cancer and dysplasia tissues but rarely in noncancerous and normal tissues .…”

Relationship of the mucosal microbiota to gastrointestinal inflammation and small cell intestinal lymphoma in cats

“…Although incompletely understood, GI inflammation‐mediated progression to cancer development might involve bacterial toxin production, release of alarmins, gut biofilm modification, dysregulation of gut barrier function, suppression of anti‐inflammatory mediators and transition through an element of high grade dysplasia to cell damage and aneuploidy 13, 19, 35, 40, 60, 61, 62…”

Crystalline structure of pulverized dental calculus induces cell death in oral epithelial cells

“…The limited expression of these pattern recognition receptors might contribute to their low sensitivity to microbial ligands. However, live bacteria in dental plaque may play more important roles in epithelial cell death than bacterial remnants in dental calculus …”

“…These epithelia act as the first line of defense against invading bacteria and other external stimuli, protecting periodontal tissue as a physical barrier . While epithelial cells are not an authentic inflammatory cell type and cannot be the dominant source of IL‐1β, they express NLRP3 inflammasome components . Upon activation of NLRP3 inflammasome, caspase‐1 cleaves a 53 kDa substrate called gasdermin D, and the N‐terminal fragment of gasdermin D assembles into pores in the cell membrane, which causes cell death, pyroptosis .…”