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Original article
A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach
  1. Christine P Petersen1,2,
  2. Anne R Meyer1,2,
  3. Carlo De Salvo3,
  4. Eunyoung Choi2,4,5,
  5. Cameron Schlegel2,5,
  6. Alec Petersen2,
  7. Amy C Engevik2,5,
  8. Nripesh Prasad6,
  9. Shawn E Levy6,
  10. R Stokes Peebles7,
  11. Theresa T Pizarro3,
  12. James R Goldenring1,2,4,5
  1. 1Departments of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, USA
  2. 2Epithelial Biology Center, Vanderbilt University, Nashville, Tennessee, USA
  3. 3Department of Pathology, Case Western Reserve School of Medicine, Cleveland, Ohio, USA
  4. 4Nashville VA Medical Center, Vanderbilt University, Nashville, Tennessee, USA
  5. 5Department of Surgery, Vanderbilt University, Nashville, Tennessee, USA
  6. 6HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
  7. 7Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
  1. Correspondence to Dr James R Goldenring, Epithelial Biology Center and Section of Surgical Sciences, Vanderbilt University Medical Center, 10435-G MRB IV, 2213 Garland Avenue, Nashville, TN 37232, USA; jim.goldenring{at}


Objective Alternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown.

Design To determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice.

Results Profiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss.

Conclusions Metaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.


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  • Contributors CPP: designed and performed experiments, analysed data and drafted manuscript. ARM, CS, AP, AE and NP: performed experiments, analysed data and revised manuscript. CDS and EC: designed and performed experiments, analysed data and revised manuscript. SEL and RSP analysed data and revised manuscript. TTP and JRG: designed experiments, analysed data and revised manuscript. All authors had access to the study data and reviewed and approved the final manuscript.

  • Funding These studies were supported by grants from a Department of Veterans Affairs Merit Review Award (I01BX000930) and NIH RO1 DK071590, as well as a grant from the Martell Foundation (to JRG), and funding from the DeGregorio Family Foundation and a Pilot & Feasibility Award from P50 CA150964 (to TTP). CPP was supported by an NIH NRSA Predoctoral Fellowship (F31 DK104600). ARM was supported by NIH T32 GM008554. This work was supported by core resources of the Vanderbilt Digestive Disease Center, (P30 DK058404) the Vanderbilt-Ingram Cancer Center (P30 CA68485, Chemical Synthesis Core), and imaging supported by both the Vanderbilt Combined Imaging Shared Resource and the Vanderbilt Digital Histology Shared Resource.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The RNA sequencing results are included in online supplementary table S1.