Macrophages have central roles in tissue homeostasis, tissue remodelling and immunity. As such, macrophages display remarkable plasticity, changing their transcriptional profile and functions based on environmental, tissue-associated and inflammatory stimuli. In addition, most tissues harbour both embryonically derived and monocyte-derived macrophages. Consequently, the classification of tissue macrophages in inflammatory conditions has become increasingly complicated. The advent of single-cell RNA sequencing (scRNA-seq) underlined the transcriptional heterogeneity of macrophages, leading to the question of whether macrophages across tissues and inflammatory conditions might have common transcriptional and functional features.
In this preprint (not peer-reviewed), Sanin et al. aim to establish a common transcriptional reference framework that defines macrophage activation states in a tissue, focusing on monocytes engrafting into the tissue. Initially, the authors created a reference dataset by characterizing the transcriptional response of adipose tissue macrophages to bacterial and helminth infections using scRNA-seq. Trajectory analysis revealed four distinct fates for monocyte differentiation in the tissue, involving ‘phagocytic’, ‘inflammatory’, ‘oxidative stress’ or ‘remodelling’ paths. Using publicly available scRNA-seq datasets across 12 tissues and 25 biological conditions, the authors could identify the same macrophage clusters and activation paths as in their reference dataset. However, in some tissues a large portion of macrophages are unclassified, which may represent macrophages in transitory stages or embryonically derived macrophages. Importantly, even if the reference dataset was only used to assign path-specific labels (without imputation of the original dataset), it was able to identify common transcriptional features and networks in each activation path. The authors validated their predictive activation paths by injection of labelled monocytes in a model of skin wound healing. These monocytes reconstituted all predictive clusters, highlighting that the activation paths seem to be specific for monocyte-derived macrophages in inflamed tissue. Lastly, a cross-tissue analysis of macrophages identified marker genes, transcriptional nodes and biological processes specific to each activation path.
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