Interleukin-9 production by type 2 innate lymphoid cells induces Paneth cell metaplasia and small intestinal remodeling

Chengyin Yuan, Aditya Rayasam, Alison Moe, Michael Hayward, Clive Wells, Aniko Szabo, Andrew Mackenzie, Nita Salzman and William R. Drobyski ()
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Chengyin Yuan: Medical College of Wisconsin
Aditya Rayasam: Medical College of Wisconsin
Alison Moe: Medical College of Wisconsin
Michael Hayward: Medical College of Wisconsin
Clive Wells: Medical College of Wisconsin
Aniko Szabo: Medical College of Wisconsin
Andrew Mackenzie: MRC Laboratory of Molecule Biology
Nita Salzman: Medical College of Wisconsin
William R. Drobyski: Medical College of Wisconsin

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Paneth cell metaplasia (PCM) typically arises in pre-existing gastrointestinal (GI) diseases; however, the mechanistic pathway that induces metaplasia and whether PCM is initiated exclusively by disorders intrinsic to the GI tract is not well known. Here, we describe the development of PCM in a murine model of chronic myelogenous leukemia (CML) that is driven by an inducible bcr-abl oncogene. Mechanistically, CML induces a proinflammatory state within the GI tract that results in the production of epithelial-derived IL-33. The binding of IL-33 to the decoy receptor ST2 leads to IL-9 production by type 2 innate lymphoid cells (ILC2) which is directly responsible for the induction of PCM in the colon and tissue remodeling in the small intestines, characterized by goblet and tuft cell hyperplasia along with expansion of mucosal mast cells. Thus, we demonstrate that an extra-intestinal disease can trigger an ILC2/IL-9 immune circuit, which induces PCM and regulates epithelial cell fate decisions in the GI tract.

Date: 2023
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DOI: 10.1038/s41467-023-43248-5

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