Holter Dorothea B, Zahalka Sophie, Brösamlen Jessica, Radhouani Mariem, Watzenboeck Martin L, Artner Tyler J, Farhat Asma, Gawish Riem, Lakovits Karin, Hladik Anastasiya, Quattrone Federica, Weninger Wolfgang, Krausgruber Thomas, Cronin Shane J F, Tikoo Shweta, Jain Rohit, Knapp Sylvia, Fortelny Nikolaus, Starkl Philipp
Research Division of Infection Biology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Research Division of Infection Biology, Department of Medicine I, Medical University of Vienna, Vienna, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
J Allergy Clin Immunol. 2025 Sep;156(3):754-773. doi: 10.1016/j.jaci.2025.02.040. Epub 2025 May 26.
Mast cells and macrophages are tissue-resident immune cells frequently found in close proximity in barrier organs. Macrophages show high plasticity and microenvironmental factors, such as cytokines, can influence their phenotype. Mast cells are central in allergic reactions where allergens cause mast cell activation via antigen-specific IgE antibodies and the release of a multitude of inflammatory substances. While macrophages have clearly defined physiologic roles in tissue maintenance and host defense against microbes, biological mast cell functions are less well defined.
In the current study, we aimed to understand the interplay of mast cells and macrophages and how mast cell-released mediators can shape macrophage phenotype and function.
Using primary in vitro models of mast cells and macrophages combined with microscopic, functional, metabolic, genetic, and epigenetic analyses, we investigate the macrophage polarization effects of mast cell mediators produced on activation with IgE and antigen. We apply a macrophage engraftment strategy to explore potential in vivo implications of mast cell-mediated priming.
We find that preformed and newly synthesized mediators released by activated mast cells shape a macrophage phenotype different from the classical M1/M2 macrophage paradigm. Exposure to supernatant of activated mast cells induces epigenetic reprogramming of macrophages. This profound priming effect strongly alters macrophage phagocytosis, cytokine production, and transcriptomic responses on secondary exposure to bacteria or their products. Importantly, in vivo transfer of primed macrophages also significantly affects the outcome of sterile inflammation and bacterial peritonitis.
Our study highlights the great potential of activated mast cells as directors of macrophage function.
肥大细胞和巨噬细胞是组织驻留免疫细胞，在屏障器官中经常紧密相邻。巨噬细胞表现出高度可塑性，细胞因子等微环境因素可影响其表型。肥大细胞在过敏反应中起核心作用，过敏原通过抗原特异性IgE抗体导致肥大细胞活化并释放多种炎症物质。虽然巨噬细胞在组织维持和宿主抵御微生物方面具有明确的生理作用，但肥大细胞的生物学功能尚不明确。
在本研究中，我们旨在了解肥大细胞与巨噬细胞之间的相互作用，以及肥大细胞释放的介质如何塑造巨噬细胞的表型和功能。
使用肥大细胞和巨噬细胞的原代体外模型，结合显微镜、功能、代谢、遗传和表观遗传分析，我们研究了用IgE和抗原激活后产生的肥大细胞介质对巨噬细胞极化的影响。我们应用巨噬细胞移植策略来探索肥大细胞介导的启动的潜在体内影响。
我们发现活化的肥大细胞释放的预先形成的和新合成的介质塑造了一种不同于经典M1/M2巨噬细胞范式的巨噬细胞表型。暴露于活化肥大细胞的上清液会诱导巨噬细胞的表观遗传重编程。这种深刻的启动效应强烈改变了巨噬细胞在再次暴露于细菌或其产物时的吞噬作用、细胞因子产生和转录组反应。重要的是，经启动的巨噬细胞的体内转移也显著影响无菌性炎症和细菌性腹膜炎的结果。
我们的研究突出了活化肥大细胞作为巨噬细胞功能指导者的巨大潜力。
