Oral argan oil attenuates gastric mucosal injury and shapes macrophage effector functions in a preclinical ethanol-induced ulcer model.

BACKGROUND: Macrophages are central to mucosal defense and key regulators of tissue homeostasis and inflammation, representing important targets for immunomodulatory strategies in gastric injury. This study investigated the modulatory effects of argan oil on macrophage effector functions, focusing on lipid droplet (LD) dynamics and macrophage extracellular trap (METosis)-associated cellular events under basal and ethanol-induced gastric ulcer conditions. METHODS: In a preclinical randomized ethanol-induced gastric ulcer model, peritoneal resident macrophages (PRMϕs), a well-established primary macrophage model, were isolated from four experimental groups: non-ulcerated controls (EIGU-/A-), argan oil-treated controls (EIGU-/A+), ethanol-induced ulcer without argan oil (EIGU+/A-), and ethanol-induced ulcer with argan oil pretreatment (EIGU+/A+). LPS-primed proinflammatory M1 PRMϕs were subsequently exposed ex vivo to gastric juices collected from the corresponding experimental groups to mimic ulcer-associated gastric microenvironmental conditions. RESULTS: Argan oil administration markedly reduced ethanol-induced gastric histological injury (p < 0.01 vs. untreated ulcer group), and potentiated ROS-dependent phagocytic activity. It enhanced METosis-associated MPO activity (p < 0.01) and differentially modulated M1(iNOS)- and M2(ARG1)-associated functional markers. Additionally, argan oil treatment markedly upregulated LD content in macrophages under both basal and ulcerative conditions. Notably, strong positive correlations between LD size and lipid content were observed across all groups (Pearson r > 0.89, p < 0.0001). Moreover, argan oil treatment significantly increased intracellular free calcium ions (ifCa2+) under both basal and ulcerative conditions, while bound intracellular calcium (bCa2+) was significantly increased under basal conditions but not under ulcerative conditions. Furthermore, argan oil treatment modulated glucose handling, as evidenced by increased intracellular glucose retention (iGLU) and reduced extracellular glucose uptake (upGLU) under both basal and ulcerative conditions (one-way ANOVA, p < 0.01). Interestingly, ulcer-derived gastric milieu significantly increased MTT-based cell metabolic viability, an effect that was partially attenuated by argan oil treatment, while both catalase activity and total cellular cholesterol content (tccCHOL)-associated trained immunity metabolic signature remained unchanged. CONCLUSION: Argan oil preserves gastric mucosal integrity under ethanol-induced ulceration and shapes macrophage effector functions, highlighting its potential translational relevance for future therapeutic strategies in gastric injury.