A unique role for IL-13 in inducing esophageal eosinophilia through MID-1 and STAT6

Jason L N Girkin; Leon A Sokulsky; Malcolm R Starkey; Philip M Hansbro; Paul S Foster; Adam M Collison; Joerg Mattes

doi:10.3389/falgy.2023.1248432

A unique role for IL-13 in inducing esophageal eosinophilia through MID-1 and STAT6

Front Allergy. 2023 Nov 6:4:1248432. doi: 10.3389/falgy.2023.1248432. eCollection 2023.

Authors

Jason L N Girkin¹, Leon A Sokulsky², Malcolm R Starkey³, Philip M Hansbro^{2

4}, Paul S Foster², Adam M Collison¹, Joerg Mattes^{1

5}

Affiliations

¹ The Priority Research Centre for Healthy Lungs and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
² The Priority Research Centre, GrowUpWellTM and The Asthma and Breathing Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
³ Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
⁴ Centre for Inflammation, Faculty of Science, School of Life Sciences, Centenary Institute and University of Technology Sydney, Sydney, NSW, Australia.
⁵ The Department of Respiratory and Sleep Medicine, John Hunter Children's Hospital, Newcastle, NSW, Australia.

Abstract

Introduction: Eosinophilic esophagitis (EoE) is associated with allergen-driven inflammation of the esophagus and an upregulated Th2 cytokine signature. Recombinant interleukin (IL)-13 (rIL-13) administration to mice induces some of the hallmark features of EoE, including increased eotaxin expression and eosinophil recruitment. Inflammation in EoE has previously been shown to depend on the expression of TRAIL and MID-1, which reduced protein phosphatase 2A (PP2A) activity. The relationship between IL-13 and TRAIL signalling in esophageal eosinophilia is currently unknown.

Objective: To investigate the interaction between IL-13-driven eosinophil infiltration and TRAIL or MID-1 in the esophagus.

Method: We administered rIL-13 to wild type (WT), TRAIL-deficient (Tnsf10^-/-) or STAT6-deficient (STAT6^-/-) mice and targeted MID-1 with small interfering RNA.

Results: rIL-13 administration to mice increased TRAIL and MID-1 expression in the esophagus while reducing PP2A activity. TRAIL deficient, but not STAT6 deficient mice demonstrated increased MID-1 expression and PP2A reduction upon IL-13 challenge which correlated with eosinophil infiltration into the esophagus. Silencing MID-1 expression with siRNA completely ablated IL-13 induced eosinophil infiltration of the esophagus, restored PP2A activity, and reduced eotaxin-1 expression.

Conclusion: IL-13-driven eosinophil infiltration of the esophagus induced eosinophilia and eotaxin-1 expression in a STAT6-dependent and MID-1-dependent manner. This study highlights a novel mechanism employed by IL-13 to perpetuate eosinophil infiltration.

Keywords: allergy; eosinophilic esophagitis; eosinophils; interleukin 13 (IL-13); midline 1 (Mid1).

Grants and funding

Supported by the National Health and Medical Research Council (NH&MRC 1011153 & 1060074 to JM), the Hunter Medical Research Institute (to AC, and JM). MS and PH are supported by fellowships from NHMRC (1072000 and 1079187).