德国波恩大学A. Schlitzer团队发现，载脂蛋白E控制单核细胞衍生的肺泡巨噬细胞，在肺β-葡聚糖诱导的炎症适应过程中依赖Dectin-1的发育。这一研究成果于2024年4月26日在线发表在国际学术期刊《自然—免疫学》上。

研究人员表示，肺部经常暴露于外界，免疫反应的最佳适应对于有效清除病原体至关重要。然而，导致肺相关巨噬细胞的功能和发育适应的机制仍然难以捉摸。

为了揭示这种机制，研究人员建立了一个环境鼻内β-葡聚糖暴露的还原模型，从而可以详细探究肺巨噬细胞适应的分子机制。通过单细胞转录组学、高维成像和流式细胞仪表征以及体内和体外挑战模型，研究人员揭示了肺部低度炎症会导致载脂蛋白 E（ApoE）依赖性单核细胞衍生肺泡巨噬细胞（ApoE⁺CD11b⁺ AM）的发育。ApoE⁺CD11b⁺ AM表达高水平的CD11b、ApoE、Gpnmb和Ccl6，具有糖酵解功能和高度吞噬能力，并在再刺激时产生大量白细胞介素-6。

功能差异是细胞内在的，骨髓细胞特异性ApoE敲除抑制了，依赖于巨噬细胞集落刺激因子分泌的Ly6c⁺单核细胞向ApoE⁺CD11b⁺ AM的分化，促进了ApoE⁺CD11b⁺ AM细胞的死亡，从而阻碍了ApoE⁺CD11b⁺ AM的维持。在体内，β-葡聚糖诱导的ApoE⁺CD11b⁺ AM限制了嗜肺军团菌感染后的细菌负荷，并改善了小鼠肺纤维化模型体内外的疾病预后。 总之，这些数据表明，在ApoE信号的控制下，根据环境线索产生的ApoE⁺CD11b⁺ AM是肺适应性增强组织复原力的重要决定因素。

附：英文原文

Title: Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation

Author: Theobald, H., Bejarano, D. A., Katzmarski, N., Haub, J., Schulte-Schrepping, J., Yu, J., Bassler, K., Ament, A. L., Osei-Sarpong, C., Piattini, F., Vornholz, L., TJonck, W., Gyrfi, A. H., Hayer, H., Yu, X., Sheoran, S., Al Jawazneh, A., Chakarov, S., Haendler, K., Brown, G. D., Williams, D. L., Bosurgi, L., Distler, J. H. W., Ginhoux, F., Ruland, J., Beyer, M. D., Greter, M., Bain, C. C., Vazquez-Armendariz, A. I., Kopf, M., Schultze, J. L., Schlitzer, A.

Issue&Volume: 2024-04-26

Abstract: The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms that lead to lung-associated macrophages’ functional and developmental adaptation remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonary macrophage adaptation. Employing single-cell transcriptomics, high-dimensional imaging and flow cytometric characterization paired with in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs). ApoE+CD11b+ AMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic, highly phagocytic and produced large amounts of interleukin-6 upon restimulation. Functional differences were cell intrinsic, and myeloid cell-specific ApoE ablation inhibited Ly6c+ monocyte to ApoE+CD11b+ AM differentiation dependent on macrophage colony-stimulating factor secretion, promoting ApoE+CD11b+ AM cell death and thus impeding ApoE+CD11b+ AM maintenance. In vivo, β-glucan-elicited ApoE+CD11b+ AMs limited the bacterial burden of Legionella pneumophilia after infection and improved the disease outcome in vivo and ex vivo in a murine lung fibrosis model. Collectively these data identify ApoE+CD11b+ AMs generated upon environmental cues, under the control of ApoE signaling, as an essential determinant for lung adaptation enhancing tissue resilience.

DOI: 10.1038/s41590-024-01830-z

Source: https://www.nature.com/articles/s41590-024-01830-z