Journal Article

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

Moe, Alison, Hayward, Michael, Mackenzie, Andrew, Drobyski, William R., Szabo, Aniko, Rayasam, Aditya, Salzman, Nita, Wells, Clive, Yuan, Chengyin

2023

Overview

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. Paneth cell metaplasia (PCM) typically arises in diseases intrinsic to the gastrointestinal tract; however, whether extra intestinal diseases can trigger PCM and the mechanistic pathway by which PCM develops is unknown. Herein, the authors show in an inducible murine model of chronic myelogenous leukaemia that a systemic inflammatory state can trigger IL-33- mediated IL-9 production that leads to small intestinal remodelling and PCM.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 14 / 14/28 / 14/5 / 14/63 / 38/22 / 38/77 / 631/250/127/1213 / 631/250/2504/2506 / 631/250/256/2516 / 631/250/347 / 64/60 / 82/80 / 82/83 / Animal models / Animals / BCR-ABL protein / Blood / Cell fate / Cells / Chronic myeloid leukemia / Colon / Cytokines / Epithelial cells / Epithelium / Esophagus / Fusion protein / Gastrointestinal diseases / Gastrointestinal system / Gastrointestinal tract / Gene expression / Granulocytes / Humanities and Social Sciences / Hyperplasia / Immunity, Innate / Inflammation / Inflammatory bowel disease / Interleukin 9 / Interleukin-33 - genetics / Interleukin-9 - genetics / Intestine / Intestine, Small / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Lymphatic system / Lymphocytes / Lymphoid cells / Mast cells / Medical schools / Metaplasia / Mice / multidisciplinary / Myeloid leukemia / Paneth Cells / Science / Science (multidisciplinary) / Small intestine / Spleen / Transplants & implants