Institute of Paediatrics, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; Department of Laboratory Medicine, The Third People's Hospital of Chengdu, Chengdu, 610031, China.
Departments of Neurology, Washington University School of Medicine and Barnes-Jewish Hospital, Saint Louis, 63110, MO, USA.
Free Radic Biol Med. 2023 Jun;202:46-61. doi: 10.1016/j.freeradbiomed.2023.03.024. Epub 2023 Mar 27.
Spasmolytic polypeptide-expressing metaplasia (SPEM), as a pre-neoplastic precursor of intestinal metaplasia (IM), plays critical roles in the development of chronic atrophic gastritis (CAG) and gastric cancer (GC). However, the pathogenetic targets responsible for the SPEM pathogenesis remain poorly understood. Gene associated with retinoid-IFN-induced mortality 19 (GRIM-19), an essential subunit of the mitochondrial respiratory chain complex I, was progressively lost along with malignant transformation of human CAG, little is known about the potential link between GRIM-19 loss and CAG pathogenesis. Here, we show that lower GRIM-19 is associated with higher NF-кB RelA/p65 and NLR family pyrin domain-containing 3 (NLRP3) levels in CAG lesions. Functionally, GRIM-19 deficiency fails to drive direct differentiation of human GES-1 cells into IM or SPEM-like cell lineages in vitro, whereas parietal cells (PCs)-specific GRIM-19 knockout disturbs gastric glandular differentiation and promotes spontaneous gastritis and SPEM pathogenesis without intestinal characteristics in mice. Mechanistically, GRIM-19 loss causes chronic mucosal injury and aberrant NRF2 (Nuclear factor erythroid 2-related factor 2)- HO-1 (Heme oxygenase-1) activation via reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation by inducing p65 nuclear translocation via an IKK/IкB partner, while NRF2-HO-1 activation contributes to GRIM-19 loss-driven NF-кB activation via a positive feedback NRF2-HO-1 loop. Furthermore, GRIM-19 loss did not cause obvious PCs loss but triggers NLRP3 inflammasome activation in PCs via a ROS-NRF2-HO-1-NF-кB axis, leading to NLRP3-dependent IL-33 expression, a key mediator for SPEM formation. Moreover, intraperitoneal administration of NLRP3 inhibitor MCC950 drastically attenuates GRIM-19 loss-driven gastritis and SPEM in vivo. Our study suggests that mitochondrial GRIM-19 maybe a potential pathogenetic target for the SPEM pathogenesis, and its deficiency promotes SPEM through NLRP3/IL-33 pathway via a ROS-NRF2-HO-1-NF-кB axis. This finding not only provides a causal link between GRIM-19 loss and SPEM pathogenesis, but offers potential therapeutic strategies for the early prevention of intestinal GC.
痉挛多肽表达化生（SPEM）作为肠化生（IM）的前瘤性前体，在慢性萎缩性胃炎（CAG）和胃癌（GC）的发展中起关键作用。然而，导致 SPEM 发病机制的致病靶点仍知之甚少。与视黄酸-IFN 诱导的死亡率 19 基因（GRIM-19）相关，它是线粒体呼吸链复合物 I 的必需亚基，随着人 CAG 的恶性转化而逐渐丢失，关于 GRIM-19 缺失与 CAG 发病机制之间的潜在联系知之甚少。在这里，我们表明，在 CAG 病变中，较低的 GRIM-19 与较高的 NF-кB RelA/p65 和 NLR 家族包含吡啶结构域 3（NLRP3）水平相关。功能上，GRIM-19 缺陷不能驱动人 GES-1 细胞在体外直接分化为 IM 或 SPEM 样细胞谱系，而壁细胞（PCs）特异性 GRIM-19 敲除扰乱胃腺分化并促进自发性胃炎和 SPEM 发病，而无肠特征在小鼠中。在机制上，GRIM-19 缺失导致慢性黏膜损伤和异常 NRF2（核因子红细胞 2 相关因子 2）-HO-1（血红素加氧酶-1）激活通过活性氧（ROS）介导的氧化应激，导致 p65 核易位通过 IKK/IKB 伴侣诱导异常 NF-кB 激活，而 NRF2-HO-1 激活通过 NRF2-HO-1 正反馈环有助于 GRIM-19 缺失驱动的 NF-кB 激活。此外，GRIM-19 缺失不会导致明显的 PCs 丢失，但通过 ROS-NRF2-HO-1-NF-кB 轴在 PCs 中触发 NLRP3 炎性小体激活，导致 NLRP3 依赖性 IL-33 表达，这是 SPEM 形成的关键介质。此外，腹腔内给予 NLRP3 抑制剂 MCC950 可显著减轻体内 GRIM-19 缺失引起的胃炎和 SPEM。我们的研究表明，线粒体 GRIM-19 可能是 SPEM 发病机制的潜在致病靶点，其缺乏通过 ROS-NRF2-HO-1-NF-кB 轴通过 NLRP3/IL-33 途径促进 SPEM。这一发现不仅提供了 GRIM-19 缺失与 SPEM 发病机制之间的因果关系，而且为早期预防肠道 GC 提供了潜在的治疗策略。
