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Interleukin-18 produced by gastric epithelial cells protects against pre-neoplastic lesions in Helicobacter pylori infection in mice

Genes & Immunity (2024)Cite this article

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IL-18 belongs to the interleukin-1 (IL-1) family of cytokines, the processing of which is mediated by multi-protein complexes, known as inflammasomes. The core components of canonical inflammasome complexes include sensor proteins (e.g. NLR family pyrin domain containing 3, NLRP3) which respond to cellular signals and bind to the adapter protein Apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD), ASC. In turn, ASC binds to pro-caspase-1 via CARD-CARD interactions, triggering the cleavage of this caspase into its active form. Bioactive caspase-1 then processes IL-1β or IL-18 into their biologically active forms. Although previous studies showed that in immune cells, H. pylori upregulates IL-18 processing via canonical NLRP3-dependent inflammasome complex [2], its processing and functional roles in epithelial cells were not known, despite both constitutive expression and H. pylori-induced upregulation of IL-18 being observed in human gastric biopsies [3]. Furthermore, it was not clear whether IL-18 was driving the inflammation or a response to it.

To bridge this knowledge gap, Tran et al. [1] addressed two key research questions:

  1. 1.

    The processing mechanism of IL-18 in gastric epithelial cells.

    First, they showed that epithelial cells are the major source of IL-18 in mouse gastric tissues and that H. pylori-induced IL-18 production is independent of the canonical NLRP3-dependent inflammasome complex but dependent on caspase-1 in primary gastric epithelial cells. Next, by knocking down/knocking out NOD1 in multiple human and mouse epithelial cell lines, they demonstrated that NOD1 is a key mediator of H. pylori-induced IL-18 processing. Interestingly, this IL-18 processing does not rely on the classical NOD1 adapter molecule Receptor-interacting protein kinase 2 (RIPK2) and downstream Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κb) signaling pathway. In contrast, evidence suggested a role for cross-talk between NOD1 and TRAF-interacting protein with forkhead-associated domain (TIFA) signaling.

    It was reported that NOD1 interacts with caspase-1 and converts it into its bioactive form to promote IL-18 processing in epithelial cells. CARD-CARD interactions between NOD1 and caspase-1 were required for maximal processing, but other interactions could also be involved. These findings were validated by multiple biochemical and imaging approaches, including fluorescence lifetime imaging microscopy-Förster resonance energy transfer (FLIM-FRET) and co-immunoprecipitation (Co-IP) assays. Nevertheless, further studies are required to confirm NOD1-caspase-1 interactions, such as by the proximity ligation assay and use of CARD-deficient forms of caspase-1. These studies are, however, impacted by the lack of high quality NOD1 antibodies. It would also be interesting to further explore the role of TIFA in NOD1-mediated IL-18 processing.

  2. 2.

    The physiopathological role of gastric epithelial cell-derived IL-18

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Fig. 1: NOD1 interacts with caspase-1 to mediate H. pylori induction of IL-18 processing in gastric epithelial cells.

References

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Authors and Affiliations

  1. Centre for Innate Immunity, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, 3168, Australia

    Xiaohu Zhao, Dongmei Tong & Richard L. Ferrero

  2. Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3800, Australia

    Xiaohu Zhao, Dongmei Tong & Richard L. Ferrero

  3. Department of Microbiology, Biomedicine Discovery Institute (3168), Monash University, Clayton, VIC, Australia

    Richard L. Ferrero

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  1. Xiaohu Zhao
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  2. Dongmei Tong
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XZ prepared manuscript drafts, with editing performed by DT and RLF.

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Correspondence to Richard L. Ferrero.

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Zhao, X., Tong, D. & Ferrero, R.L. Interleukin-18 produced by gastric epithelial cells protects against pre-neoplastic lesions in Helicobacter pylori infection in mice. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00253-y

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