Amélie Grosjean, Aude Jalon, Claire Leveau, Marc Diedisheim, David Alejandro Bejarano, Joyceline Cuenco, Kevin Mulder, Zhaoyuan Liu, Audrey Le Guernic, Marie‐Laure Island, Jarne Walckiers, Gamze Ates, Clément Materne, Andreia Goncalves, Ivan Nemazanyy, Laura G. Baudrin, Sylvain Baulande, Martine Ropert, Jean–François Gautier, Ahmed Hamaï, Andreas Schlitzer, Florent Ginhoux, Ann Massie, Nicolas Venteclef, Élise Dalmas
Pancreatic islet-resident macrophages (IRMs) display an activated phenotype and contribute to islet development and remodeling, yet their origin, heterogeneity, and functional roles remain poorly understood. Using complementary fate-mapping systems, we show that, in adult mice, around half of IRMs originate from circulating monocytes and undergo minimal turnover. Integrated multiple single-cell RNA sequencing analyses of mouse and human islets identified four major IRM cell states that collectively reveal their inflammatory and metabolic activation. Among these, a transcriptional program driven by the cystine-glutamate antiporter SLC7A11 and enriched in CD9 high IRMs was associated with enhanced antioxidant defense, mitochondrial activity, and iron-lipid metabolic pathways. We found that Slc7a11 -expressing IRMs preserve β cell redox homeostasis and insulin secretion, both at baseline and under stress. These findings position IRMs as specialized immune sentinels in the endocrine pancreas and identify SLC7A11 as a key macrophage-intrinsic safeguard against oxidative stress, with broad implications for islet resilience and metabolic health.