IL33 Is a Stomach Alarmin That Initiates a Skewed Th2 Response to Injury and Infection

Abstract

Background & AimsInterleukin (IL)33 is a recently described alarmin that is highly expressed in the gastric mucosa and potently activates Th2 immunity. It may play a pivotal role during Helicobacter pylori infection. Here, we delineate the role of IL33 in the normal gastric mucosa and in response to gastropathy.MethodsIL33 expression was evaluated in mice and human biopsy specimens infected with H pylori and in mice after dosing with aspirin. IL33 expression was localized in the gastric mucosa using immunofluorescence. Mice were given 1 or 7 daily doses of recombinant IL33 (1 μg/dose), and the stomach and the spleen responses were quantified morphologically, by flow cytometry and using quantitative reverse-transcription polymerase chain reaction and immunoblotting.ResultsIn mice, the IL33 protein was localized to the nucleus of a subpopulation of surface mucus cells, and co-localized with the surface mucus cell markers Ulex Europaeus 1 (UEA1), and Mucin 5AC (Muc5AC). A small proportion of IL33-positive epithelial cells also were Ki-67 positive. IL33 and its receptor Interleukin 1 receptor-like 1 (ST2) were increased 4-fold after acute (1-day) H pylori infection, however, this increase was not apparent after 7 days and IL33 expression was reduced 2-fold after 2 months. Similarly, human biopsy specimens positive for H pylori had a reduced IL33 expression. Chronic IL33 treatment in mice caused systemic activation of innate lymphoid cell 2 and polarization of macrophages to the M2 phenotype. In the stomach, IL33-treated mice developed transmural inflammation and mucous metaplasia that was mediated by Th2/signal transducer and activator of transcription 3 signaling. Rag-1-/- mice, lacking mature lymphocytes, were protected from IL33-induced gastric pathology.ConclusionsIL33 is highly expressed in the gastric mucosa and promotes the activation of T helper 2–cytokine–expressing cells. The loss of IL33 expression after prolonged H pylori infection may be permissive for the T helper 1–biased immune response observed during H pylori infection and subsequent precancerous progression.

Regulatory T Cells Control Th2-Dominant Murine Autoimmune Gastritis

“…It is possible that factors and cytokines operating locally in the stomach also influence the expression of a Th2-dominant tissue response. For example, Buzzelli et al showed that IL-33 promoted a type 2 gastric inflammatory response in WT mice that resembles the AIG in DEREG mice (120). …”

Regulation of Gastric Carcinogenesis by Inflammatory Cytokines

“…Several additional cytokines are reported to be expressed in the inflamed gastric mucosa, including IL10, IL32, and IL33 43, 44, 45. Additional information is needed to understand how the complex milieu of cytokines that are present in an individual with chronic gastritis influences the risk of gastric cancer (Table 1).…”

Murine Models of Gastric Corpus Preneoplasia

“…The mechanism by which Helicobacter causes parietal cell loss is not known. The host inflammatory response, however, is thought to be critical both in human beings and in mouse models 3, 36, 63, 64, 65. In general, the immune response can be categorized along 2 distinct paradigms: innate and adaptive.…”

“…IL33 synergizes to promote a Th2 inflammatory response that activates innate and adaptive immune cells. IL33 generally is classified as an alarmin because of its release into the extracellular environment by necrotic or apoptotic cells 64 . IL33-treated mice develop SPEM and a robust inflammatory response in the lungs, intestine, and stomach, indicating that IL33 is sufficient to recruit inflammatory cells and drive mucous production within respiratory and gut epithelial tissue 64, 119.…”

“…IL33 generally is classified as an alarmin because of its release into the extracellular environment by necrotic or apoptotic cells 64 . IL33-treated mice develop SPEM and a robust inflammatory response in the lungs, intestine, and stomach, indicating that IL33 is sufficient to recruit inflammatory cells and drive mucous production within respiratory and gut epithelial tissue 64, 119. However, IL33 is expressed only in the normal stomach by cells in the surface cell (upper pit/foveolar) zone in the corpus, and those cells are not thought to undergo cell death during Helicobacter infection.…”