School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Front Endocrinol (Lausanne). 2022 Jul 12;13:858422. doi: 10.3389/fendo.2022.858422. eCollection 2022.
Pancreatic resident macrophages, a heterogeneous family of cells with distinct origins and phenotypes, are the main myeloid cells in exocrine and endocrine tissues. Adult exocrine F4/80 macrophages consist of three different subsets based on the embryonic marker Tim-4 and MHC II expression. Their frequencies shift during aging and obesity with the Tim-4MHCII fraction becoming the predominant subpopulation in the inter acinar stroma. Endocrine resident F4/80 macrophages are more homogenous and represent the prevalent leukocyte fraction residing within the islets in both lean and obese mice. We used an adult fate mapping mouse model to characterize turnover kinetics within the pancreatic resident macrophages under normal homeostasis and obese diabetic conditions. We demonstrate that islet resident macrophages show unique replenishment kinetics, with embryonic macrophages being gradually replaced by bone marrow-derived monocytes with increasing age. Their replenishment was independent of the CCL2/CCR2 axis. Furthermore, we confirmed that both exocrine Tim-4MHCII and Tim-4MHCII fractions are long-lived and primarily independent from bone marrow-derived monocytes. In contrast, exocrine Tim-4MHCII macrophages are gradually replaced through a CCR2-dependent influx of bone marrow-derived monocytes in aging. Moreover, we show that obesity and type 2 diabetes do not affect the turnover kinetics of any macrophage subpopulation residing in the pancreas. Our study uncovers new insights on pancreatic macrophage biology in aging and obesity.
胰腺固有巨噬细胞是具有不同起源和表型的异质性细胞家族，是外分泌和内分泌组织中的主要髓系细胞。成年外分泌 F4/80 巨噬细胞根据胚胎标志物 Tim-4 和 MHC II 表达分为三个不同亚群。它们的频率在外分泌和肥胖过程中发生变化，Tim-4MHCII 亚群在外分泌组织的腺泡间基质中成为主要亚群。内分泌固有 F4/80 巨噬细胞更具同质性，代表在肥胖和瘦小鼠胰岛内居住的主要白细胞群。我们使用成年命运图谱小鼠模型来研究在正常生理状态和肥胖糖尿病条件下胰腺固有巨噬细胞的更新动力学。我们证明胰岛固有巨噬细胞具有独特的补充动力学，随着年龄的增长，胚胎巨噬细胞逐渐被骨髓来源的单核细胞取代。它们的补充与 CCL2/CCR2 轴无关。此外，我们证实，外分泌的 Tim-4MHCII 和 Tim-4MHCII 亚群均具有较长的寿命，主要与骨髓来源的单核细胞无关。相比之下，在外分泌 Tim-4MHCII 巨噬细胞中，随着年龄的增长，CCR2 依赖性的骨髓来源单核细胞的流入逐渐取代了这些巨噬细胞。此外，我们表明肥胖和 2 型糖尿病并不影响胰腺内任何巨噬细胞亚群的更新动力学。我们的研究揭示了衰老和肥胖过程中胰腺巨噬细胞生物学的新见解。
