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

Jon N Buzzelli; Heather V Chalinor; Daniel I Pavlic; Philip Sutton; Trevelyan R Menheniott; Andrew S Giraud; Louise M Judd

doi:10.1016/j.jcmgh.2014.12.003

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

Cell Mol Gastroenterol Hepatol. 2015 Jan 3;1(2):203-221.e3. doi: 10.1016/j.jcmgh.2014.12.003. eCollection 2015 Mar.

Authors

Jon N Buzzelli¹, Heather V Chalinor², Daniel I Pavlic², Philip Sutton³, Trevelyan R Menheniott², Andrew S Giraud¹, Louise M Judd¹

Affiliations

¹ Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.
² Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
³ Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Centre for Animal Biotechnology, School of Veterinary Science, University of Melbourne, Parkville, Victoria, Australia.

Abstract

Background & aims: Interleukin (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.

Methods: IL33 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.

Results: In 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.

Conclusions: IL33 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.

Keywords: AB, Alcian blue; DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal–regulated kinase; FBS, fetal bovine serum; Gastric Cancer; HBSS, Hank’s balanced salt solution; Helicobacter pylori; IL, interleukin; IL33; ILC, innate lymphoid cell; Inflammatory Response; NF-κB, nuclear factor-κB; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; QRT-PCR, quantitative reverse-transcription polymerase chain reaction; SMC, surface mucus cells; SPF, specific pathogen free; SS1, Sydney strain 1; STAT, signal transducer and activator of transcription; TFF, trefoil factor; Th, T-helper; WT, wild type; mRNA, messenger RNA.