LAUSR

Peptic ulcer disease is a frequent clinical problem with potentially serious complications such as bleeding or perforation. A decisive factor in the pathogenesis of peptic ulcers is gastric acid, the secretion of which is controlled by the hormone gastrin released from gastric G cells. However, the molecular mechanisms regulating gastrin plasma concentrations are poorly understood. Here, we identified a semaphorin-plexin signaling pathway that operates in gastric G cells to inhibit gastrin expression on a transcriptional level, thereby limiting food-stimulated gastrin release and gastric acid secretion. Using a systematic siRNA screening approach combined with biochemical, cell biology, and in vivo mouse experiments, we found that the RasGAP protein Rasal1 is a central mediator of plexin signal transduction, which suppresses gastrin expression through inactivation of the small GTPase R-Ras. Moreover, we show that Rasal1 is pathophysiologically relevant for the pathogenesis of peptic ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs), a main risk factor of peptic ulcers in humans. Last, we show that application of recombinant semaphorin 4D alleviates peptic ulcer disease in mice in vivo, demonstrating that this signaling pathway can be harnessed pharmacologically. This study unravels a mode of G cell regulation that is functionally important in gastric homeostasis and disease. Description Semaphorin-induced activation of plexin-Rasal1 signaling lowers gastric acid production and alleviates NSAID-induced gastroduodenal ulcers. Easing gastric acid Proton pump inhibitors are commonly used to treat gastric acid–related issues, but these drugs may have serious long-term side effects. Xu et al. show that semaphorin-plexin-RasGAP signaling represses gastrin mRNA expression and food-induced gastric acid secretion. Intravenous administration of semaphorin 4D ameliorated nonsteroidal anti-inflammatory drug–induced peptic ulcers in mouse models. This paper establishes a signaling axis that may help in the treatment of peptic ulcer disease.