Aim2-mediated/IFN-β–independent regulation of gastric metaplastic lesions via CD8+ T cells

Abstract

Aim2 deletion exacerbates SPEM. We identified Aim2 in a screen of upregulated gastric genes in 2 mouse models of SPEM: (a) chronic (6-month) H. felis infection and (b) gastric tissue-specific overexpression of IFN-γ (H + / K +-ATPase-IFN-γ) (18) (Figure 1A). The upregulation of Aim2 in gastric tissue of chronically H. felis-infected mice at 6 months was corroborated by real-time quantitative PCR (RT-qPCR) (Figure 1B). To study the role of Aim2 in SPEM, we used mice deficient in Aim2 (B6.129P2-Aim2 Gt(CSG445)Byg /J; Aim2-/-) and chronically infected them with H. felis. We confirmed that Aim2 deletion abrogated Aim2 expression in the stomach (Figure 1B). Aim2 deficiency worsened gastric immunopathology (Figure 1C), increased stomach weight (Figure 1D), exacerbated SPEM (Figure 1, E and F), and enhanced parietal cell atrophy (Figure 1G). All the latter characteristics epitomize features of enhanced gastric preneoplastic development in Aim2-/mice. Aim2 lacks a significant effect on gastric inflammasome activity. Because Aim2 functions as a component of the inflammasome (13-15), we investigated whether Aim2 was mediating its observed effects by regulating IL-1β and IL-18 secretion. We found gastric explants from 6-month infected Aim2-/stomachs did not show a significant effect on the secretion of IL-1β or IL-18 (Supplemental Figure 1, A and B; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.94035DS1). Hence, these observations did not provide mechanistic insight into how the loss of Aim2 led to increased SPEM. This prompted us to dissect the mechanism of how Aim2 inhibits SPEM further. Aim2 is not required for the expression of the inhibitory Fcγ receptor. Because a previous report showed that Aim2 is necessary for the expression of the inhibitory Fcγ receptor (FcγRIIB) (19), we investigated a possible alternative mechanism for Aim2 via this protein. FcγRIIB is a lupus susceptibility protein that suppresses antibody production in B cells (20) and blocks maturation of dendritic cells (21). However, we did not observe a significant effect of Aim2 deficiency on FcγRIIB expression in the inflamed stomach (Supplemental Figure 1C). Aim2 deficiency increases gastric CD8 + T cell frequency in the chronically inflamed stomach. Because the mechanism of Aim2 in gastric pathology remained unclear, we screened several gastric immune populations from chronically infected Aim2-/stomachs versus WT stomachs. Previous reports have documented several immune subtypes that increase during chronic gastric inflammation and SPEM (22-28). These include CD11b + Ly6G + myeloid-derived suppressor cells (MDSCs) (22-24), CD11b + Ly6Gmyeloid cells (22), CD4 + and CD8 + T cells (25-27), and B220 + IgM + B cells (28). We therefore screened these populations in our system (Figure 2A). In chronically infected WT stomachs, we observed a significant increase in all these populations relative to uninfected WT stomachs (Figure 2A). However, gastric CD8 + T cells were the only population whose frequency was affe...

Review ‐ Helicobacter, inflammation, immunology and vaccines

“…These changes were induced by CXCL16 from B cells. The authors concluded that Aim2 regulates CD8 + T‐cell infiltration independently of the inflammasome, and inhibits metaplasia via a novel mechanism 9 . Lv et al 7 also reported that gastric epithelial cell expression of MMP‐10 led to CXCL16‐mediated migration of CD8 + T cells into the H pylori‐ infected gastric mucosa.…”

The Emerging Relevance of AIM2 in Liver Disease

“…Not only in epithelial cells, but also in immune cells, AIM2 seems to have inflammasome-unrelated functions during gastrointestinal disease. A recent report showed that AIM2 indirectly regulates gastric CD8 + T cell frequency during gastritis [ 88 ]. This effect is mediated by AIM2 expression in B cells, where it suppresses CXCL16 production, reducing the accumulation of CD8 + T cells in the inflamed gastric mucosa [ 88 ].…”

“…A recent report showed that AIM2 indirectly regulates gastric CD8 + T cell frequency during gastritis [ 88 ]. This effect is mediated by AIM2 expression in B cells, where it suppresses CXCL16 production, reducing the accumulation of CD8 + T cells in the inflamed gastric mucosa [ 88 ]. Furthermore, inflammasomes-independent functions of AIM2 have also been observed outside the gastrointestinal tract.…”

Review: Other Helicobacter species

“…Moreover, they showed that MiR130b plays an essential role in supporting metaplastic transformation and MDSC function 27 . El‐Zaatari et al demonstrated a novel function of absent in melanoma 2 (Aim2) that regulates gastric metaplastic lesions via CXCL16‐mediated CD8 + T cells during H. felis infection 28 . Another study investigated how β‐catenin signaling regulates the tumour immune microenvironment in the stomach using a murine gastric cancer model established by H. felis .…”