Institute of Biochemistry I, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.
Department of Experimental Nephrology, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
Lab Invest. 2018 Nov;98(11):1408-1422. doi: 10.1038/s41374-018-0098-4. Epub 2018 Aug 7.
Macrophage-epithelial cross-talk regulates cell cycle progression and represents an important factor in rescuing epithelial cells from cell cycle arrest in order to maintain a healthy epithelial phenotype. However, the underlying mechanisms are still not well defined. We provide evidence that macrophage-secreted lipocalin-2 (Lcn-2) plays a key role during this process. In a co-culture setup using cell cycle arrested NRK52e renal epithelial cells and primary bone marrow-derived macrophages, Lcn-2 restores proliferation through inhibition of peroxisome proliferator-activated receptor (PPAR)-γ. Lcn-2 overexpression in macrophages overcomes epithelial cell cycle arrest and enhances epithelial markers via megalin and the downstream activation of PI3K/Akt signalling pathway, whereas a knockdown of Lcn-2 in macrophages prevented this effect. Our results show that macrophage-secreting Lcn-2 is crucial in rescuing epithelial cells from cell cycle arrest and in promoting epithelial proliferation.
巨噬细胞-上皮细胞相互作用调节细胞周期进程，是挽救细胞周期阻滞的上皮细胞以维持健康上皮表型的重要因素。然而，其潜在机制仍未得到明确界定。我们提供的证据表明，巨噬细胞分泌的脂钙蛋白 2（Lcn-2）在这一过程中起着关键作用。在使用细胞周期阻滞的 NRK52e 肾上皮细胞和原代骨髓来源的巨噬细胞的共培养体系中，Lcn-2 通过抑制过氧化物酶体增殖物激活受体（PPAR）-γ来恢复增殖。巨噬细胞中 Lcn-2 的过表达克服了上皮细胞的细胞周期阻滞，并通过 megalin 增强上皮标记物和下游激活的 PI3K/Akt 信号通路，而巨噬细胞中 Lcn-2 的敲低则阻止了这种作用。我们的结果表明，巨噬细胞分泌的 Lcn-2 对于挽救细胞周期阻滞的上皮细胞和促进上皮细胞增殖至关重要。
