A common framework of monocyte-derived macrophage activation

Abstract

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.

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

“…Interestingly, transient expression of Retnla was recently shown in nearly all tissue-resident macrophages and its induction in PEC macrophages was not IL-4ra-dependent. 56 Consistent with this, other studies report that RELMα is induced by signals other than Th2 cytokines, such as hypoxia or phagocytosis of apoptotic cells. 57,58 Our findings support the differential induction of canonical M[IL-4] genes, and identify choline metabolism as a specific inducer of Retnla .…”

Single-cell profiling identifies ACE+granuloma macrophages as a non-permissive niche for intracellular bacteria during persistentSalmonellainfection

“…The ACE + granuloma macrophages described here are characterized by their expression of lineage markers CD11b, CD11c, and Ly6C, which is expressed at lower level compared to classical monocytes (Fig. S1B-C), suggesting that they may be monocyte-derived macrophages(72). It is now well recognized that in almost all tissues, some macrophages originate from blood-borne monocytic precursors recruited to the tissues during steady state or in the setting of inflammation; whereas, other macrophages arise from embryonic origin during development(30).…”

Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy

“…Last-generation technologies (such as sc-RNA-seq and CYTOF) dramatically improved our current understanding of myeloid cell ontogeny and functional polarisation in cancer [ 61 , 62 ] and other pathologies. To solve the myeloid-cell puzzle, Sanin and colleagues established a predictive macrophage activation model across 12 tissues and 25 biological conditions, in mice, and identified shared and unique functional pathways [ 63 ]. Moreover, TME deconvolution of about 210 patients across 15 human cancers identified many different subsets of TAMs with mixed M1/M2 signatures [ 64 ].…”