Sound the Alarmin: Interleukin-33 Commandeers the Gastric Immune Response

nterleukin-33 (IL-33) is a member of the IL-1 superIfamily and activates group 2 innate lymphoid cells (ILC2), mast cells, and their progenitors. Studies indicate that ILCs, which secrete copious amounts of IL-5 and IL-13 in response to IL-33, play critical roles in directing the development of type-2 immunity and allergic inflammation. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Buzzelli et al provide novel insights into the role that IL-33 exerts on the gastric immune response to infection with the pathogen Helicobacter pylori. Chronic H. pylori-induced gastritis is mediated by a variety of constituents, including gastric epithelial cells, neutrophils, macrophages, and dendritic cells that lead to a TH1-biased lymphocyte response. One microbial determinant that augments gastric cancer risk is the cag pathogenicity island, and cagþ strains significantly increase the risk for severe gastritis, atrophic gastritis, and cancer compared with strains lacking the cag island. Another H. pylori factor, neutrophil-activating protein, promotes neutrophil recruitment, contributes to TH1 polarization by stimulating both IL-12 and IL-23, and influences the production of TH1 cells, resulting in increased production of interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), and cytolytic activity of T helper (TH) cells. 3 H. pylori also activates macrophages, resulting in the production of IL-1 and TNF-a, in turn, promoting a TH1-directed response. Dendritic cells (DCs) represent a critical bridge between the innate and adaptive immune responses. In response to H. pylori, DCs drive TH1-effector responses, leading to production of TNF-a, IFN-g, and IL-2. Consistent with a TH1-type cytokine response, gastric lymphocyte populations from H. pylori-infected patients harbor IFN-gproducing T cells; after stimulation, these cells produce abundant levels of the TH1 cytokines IFN-g and IL-2 and low levels of the TH2 cytokines IL-4 and IL-5. 6 Collectively, the host immune response to H. pylori is predominantly a TH1-type response, which leads to the development of a chronic inflammatory infiltrate that fails to eliminate this pathogen. Buzzelli et al demonstrate that IL-33 expression is increased in response to acute H. pylori infection but is reciprocally suppressed during chronic H. pylori infection in mice and humans, which contributes to the dominant TH1polarized phenotype observed within infected gastric mucosa. To define the gastric response to IL-33 per se, mice were treated with recombinant IL-33. Chronic IL-33 administration led to increased gastric inflammation and the development of atrophy and metaplasia. Using flow cytometry to characterize immune cell populations in response to IL-33, the authors demonstrated no differences