Injury, repair, inflammation and metaplasia in the stomach

Abstract

The development of intestinal-type gastric cancer is preceded by the emergence of metaplastic cell lineages in the gastric mucosa. In particular, intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia (SPEM) have been associated with the pathological progression to intestinal-type gastric cancer. The development of SPEM represents a physiological response to damage that recruits reparative cells to sites of mucosal injury. Metaplastic cell lineages are characterized by mucus secretion, adding a protective barrier to the epithelium. Increasing evidence indicates that the influence of alarmins and cytokines is required to initiate the process of metaplasia development. In particular, IL-33 derived from epithelial cells stimulates IL-13 production by specialized innate immune cells to induce chief cell transdifferentiation into SPEM following the loss of parietal cells from the corpus of the stomach. While SPEM represents a physiological healing response to acute injury, persistent injury and chronic inflammation can perpetuate a recurring pattern of reprogramming and metaplasia that is a risk factor for gastric cancer development. The transdifferentiation of zymogen secreting cells into mucous cell metaplasia may represent both a general repair mechanism in response to mucosal injury in many epithelia as well as a common pre-neoplastic pathway associated with chronic injury and inflammation.

Keywords: IL-13; IL-33; SPEM; ST2; macrophage polarization; spasmolytic polypeptide-expressing metaplasia; transdifferentiation.

Figure 1. Schematic diagram of the normal mammalian stomach corpus gland and epithelial reprogramming into SPEM following damage

Epithelial damage in the acid‐secreting region of the stomach known as the corpus results in the replacement of normal cell lineages with a metaplastic cell lineage designated SPEM. Damage, such as parietal cell loss, is also associated with expansion of mucus‐secreting foveolar cells. SPEM (yellow cells in the metaplastic gland at right) develops via the transdifferentiation of chief cells (green cells in the normal corpus gland at left) and is characterized by a distinct gene expression profile and protein signature, as well as the production of mucus granules containing Muc6 and TFF2. The SPEM lineage is reminiscent of mucus‐producing cells found in deep antral glands. Mucus‐secreting metaplastic cells develop to protect and fuel the repair of the stomach.

Figure 2. The coordinated regulation of metaplasia development

IL‐33 functions as an alarmin released from foveolar epithelial cells following damage to the mucosa, such as parietal cell loss. The IL‐33 receptor (ST2) is expressed on the surface of a variety of tissue‐resident immune cell populations. However, in this case, we hypothesize that type II innate lymphoid cells (ILC2s) respond to IL‐33 by producing type II cytokines including IL‐13. IL‐13 signalling downstream of IL‐33 drives SPEM formation and alternative activation of macrophages. Alternatively activated macrophages subsequently promote the advancement of SPEM to a more proliferative metaplasia and produce IL‐33 which may further promote IL‐13 release.