Huang Hao, Balzer Nora R, Seep Lea, Splichalova Iva, Blank-Stein Nelli, Viola Maria Francesca, Franco Taveras Eliana, Acil Kerim, Fink Diana, Petrovic Franzisca, Makdissi Nikola, Bayar Seyhmus, Mauel Katharina, Radwaniak Carolin, Zurkovic Jelena, Kayvanjoo Amir H, Wunderling Klaus, Jessen Malin, Yaghmour Mohamed H, Kenner Lukas, Ulas Thomas, Grein Stephan, Schultze Joachim L, Scott Charlotte L, Guilliams Martin, Liu Zhaoyuan, Ginhoux Florent, Beyer Marc D, Thiele Christoph, Meissner Felix, Hasenauer Jan, Wachten Dagmar, Mass Elvira
Developmental Biology of the Immune System, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
Computational Life Sciences, Life and Medical Sciences (LIMES) Institute and Bonn Center for Mathematical Life Sciences, University of Bonn, Bonn, Germany.
Nature. 2025 Jun 18. doi: 10.1038/s41586-025-09190-w.
Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-α (HIF1α) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases.
库普弗细胞（KCs）是定居于组织的巨噬细胞，在胚胎发育早期就定植于肝脏。在定植于肝脏后，库普弗细胞迅速获得组织特异性转录特征，随着肝脏发育而成熟并适应其功能。在整个发育和成年期，库普弗细胞执行对肝脏和机体稳态至关重要的独特核心功能，包括支持胎儿红细胞生成、出生后红细胞循环和肝脏代谢。然而，发育过程中巨噬细胞核心功能的扰动是否会导致出生后阶段的疾病或对疾病产生影响，目前尚不清楚。在此，我们利用母体肥胖的小鼠模型在妊娠期扰乱库普弗细胞的功能。我们发现，暴露于母体肥胖的后代会发展为脂肪肝疾病，这是由库普弗细胞异常的发育编程驱动的，这种编程会持续到成年期。编程后的库普弗细胞通过载脂蛋白分泌促进肝细胞摄取脂质。对肥胖母亲所生新生小鼠的库普弗细胞进行清除，然后用幼稚单核细胞进行补充，可挽救脂肪肝疾病。此外，在妊娠期巨噬细胞中对编码缺氧诱导因子-α（HIF1α）的基因进行基因敲除，可防止库普弗细胞的代谢编程从氧化磷酸化转变为糖酵解，从而避免脂肪肝疾病的发展。这些结果确定了库普弗细胞功能的发育扰动是成年期脂肪肝疾病的一个致病因素，并将胎儿来源的巨噬细胞定位为健康与疾病发育起源概念中的关键代际信使。
