Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disconnected picture of macrophage biology that has emerged from these observations is a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a notable commonality and finite number of transcriptional profiles, in particular among infiltrating macrophages, which we modeled as defined stages along four conserved activation paths. These activation paths include a “phagocytic” regulatory path, an “inflammatory” cytokine-producing path, an “oxidative stress” antimicrobial path, or a “remodeling” extracellular matrix deposition path. We verified this model with adoptive cell transfer experiments and identified transient RELMɑ expression as a feature of monocyte-derived macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of monocyte-derived macrophage activation in inflammation and homeostasis.

中文翻译：

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单核细胞衍生巨噬细胞活化的共同框架

在稳态和疾病期间，巨噬细胞遍布每个器官，显示出组织印记和异质激活的特征。从这些观察中出现的巨噬细胞生物学的不连贯图景是跨模型整合或与体外巨噬细胞激活范式整合的障碍。我们着手将小鼠组织和炎症条件下的巨噬细胞异质性背景化，特别是旨在定义一个共同的巨噬细胞激活框架。我们建立了一个预测模型，我们用该模型绘制了 12 个组织和 25 种生物条件下巨噬细胞的激活图，发现了显着的共性和有限数量的转录谱，特别是在浸润性巨噬细胞中，我们将其建模为沿四个保守激活路径的定义阶段。这些激活途径包括“吞噬”调节途径、“炎症”细胞因子产生途径、“氧化应激”抗菌途径或“重塑”细胞外基质沉积途径。我们通过过继细胞转移实验验证了该模型，并将瞬时 RELMɑ 表达确定为单核细胞衍生的巨噬细胞组织植入的特征。我们提出，这种巨噬细胞分类的综合方法允许建立一个共同的预测框架，用于在炎症和体内平衡中单核细胞衍生的巨噬细胞活化。我们通过过继细胞转移实验验证了该模型，并将瞬时 RELMɑ 表达确定为单核细胞衍生的巨噬细胞组织植入的特征。我们提出，这种巨噬细胞分类的综合方法允许建立一个共同的预测框架，用于在炎症和体内平衡中单核细胞衍生的巨噬细胞活化。我们通过过继细胞转移实验验证了该模型，并将瞬时 RELMɑ 表达确定为单核细胞衍生的巨噬细胞组织植入的特征。我们提出，这种巨噬细胞分类的综合方法允许建立一个共同的预测框架，用于在炎症和体内平衡中单核细胞衍生的巨噬细胞活化。