Characterizing caspase-1 involvement during esophageal disease progression

Abstract

Barrett's esophagus (BE) is an inflammatory condition and a neoplastic precursor to esophageal adenocarcinoma (EAC). Inflammasome signaling, which contributes to acute and chronic inflammation, results in caspase-1 activation leading to the secretion of IL-1β and IL-18, and inflammatory cell death (pyroptosis). This study aimed to characterize caspase-1 expression, and its functional importance, during disease progression to BE and EAC.Three models of disease progression (Normal-BE-EAC) were employed to profile caspase-1 expression: (1) a human esophageal cell line model; (2) a murine model of BE; and (3) resected tissue from BE-associated EAC patients. BE patient biopsies and murine BE organoids were cultured ex-vivo in the presence of a caspase-1 inhibitor, to determine the importance of caspase-1 for inflammatory cytokine and chemokine secretion. Epithelial caspase-1 expression levels were significantly enhanced in BE (p<0.01). In contrast, stromal caspase-1 levels correlated with histological inflammation scores during disease progression (p<0.05). Elevated secretion of IL-1β from BE explanted tissue, compared to adjacent normal tissue (p<0.01), confirmed enhanced activity of caspase-1 in BE tissue.Caspase-1 inhibition in LPS-stimulated murine BE organoids caused a significant reduction in IL-1β (p<0.01) and CXCL1 (p<0.05) secretion, confirming the importance of caspase-1 in the production of cytokines and chemokines associated with disease progression from BE to EAC.Targeting caspase-1 activity in BE patients should therefore be tested as a novel strategy to prevent inflammatory complications associated with disease progression.

Pyroptosis, a new bridge to tumor immunity

“…Barrett's esophagus (BE) can also activate caspase-1-dependent pyroptosis and cause the release of IL-1β and IL-18 to enhance the progression of esophageal cancer. 33 Additionally, Gao et al 34 formation. NLRP3 can stimulate pyroptosis and the release mature IL-1β or IL-18 to decelerate host immunity in gastric tumorigenesis.…”

“…Barrett's esophagus (BE) can also activate caspase‐1‐dependent pyroptosis and cause the release of IL‐1β and IL‐18 to enhance the progression of esophageal cancer. 33 Additionally, Gao et al 34 described a novel mechanism by which GSDMD‐mediated pyroptosis may aid non‐small‐cell lung cancer (NSCLC) to evade the innate immune response through the dysregulation of immunomodulatory factors, such as IL‐1β. The report published by Pachathundikandi et al reiterated that Helicobacter pylori , which always colonizes in the stomach, could promote NLRP3 inflammasome formation.…”

“…Furthermore, Wang et al 32 showed that the accumulation of alcohol in the esophagus could trigger caspase‐1‐mediated pyroptosis and the release of IL‐1β and IL‐18, which may be involved in esophageal cancer. Barrett's esophagus (BE) can also activate caspase‐1‐dependent pyroptosis and cause the release of IL‐1β and IL‐18 to enhance the progression of esophageal cancer 33 . Additionally, Gao et al 34 described a novel mechanism by which GSDMD‐mediated pyroptosis may aid non‐small‐cell lung cancer (NSCLC) to evade the innate immune response through the dysregulation of immunomodulatory factors, such as IL‐1β.…”

Identification of TLR2 Signalling Mechanisms Which Contribute to Barrett’s and Oesophageal Adenocarcinoma Disease Progression

“…Tissue from the cardia region at the squamous-columnar junction (SCJ) of 12-month old L2-IL-1B mice was processed for 3D organoid culture in Matrigel for 3 weeks, as previously described [ 20 , 21 ]. Three days before harvesting, organoids were pre-treated (1 h) with the αTLR2 neutralising antibody (10 μg/mL) followed by 24 h stimulation with P2C (40 ng/mL).…”

Cell pyroptosis in health and inflammatory diseases

“…Caspase-1 mediates the inflammatory disease BE, which can further develop into EAC. Barber et al showed that the secretion of inflammatory cytokines and chemokines is reduced in BE patient biopsies and in mouse BE organ cultures in vitro via inhibition of caspase-1 [ 81 ]. The expression of caspase-activated GSDMD is beneficial for inhibiting the proliferation of gastric cancer cells.…”