The gene signature of activated M-CSF-primed human monocyte-derived macrophages is IL-10-dependent

14 p.-5 fig.During inflammatory responses, monocytes are recruited into inflamed tissues, where they become monocyte-derived macrophages and acquire pro-inflammatory and tissue-damaging effects in response to the surrounding environment. In fact, monocyte-derived macrophage subsets are major pathogenic cells in inflammatory pathologies. Strikingly, the transcriptome of pathogenic monocyte-derived macrophage subsets resembles the gene profile of macrophage colony-stimulating factor (M-CSF)-primed monocyte-derived human macrophages (M-MØ). As M-MØ display a characteristic cytokine profile after activation (IL10high TNFlow IL23low IL6low), we sought to determine the transcriptional signature of M-MØ upon exposure to pathogenic stimuli. Activation of M-MØ led to the acquisition of a distinctive transcriptional profile characterized by the induction of a group of genes (Gene set 1) highly expressed by pathogenic monocyte-derived macrophages in COVID-19 and whose presence in tumor-associated macrophages (TAM) correlates with the expression of macrophage-specific markers (CD163, SPI1) and IL10. Indeed, Gene set 1 expression was primarily dependent on ERK/p38 and STAT3 activation, and transcriptional analysis and neutralization experiments revealed that IL-10 is not only required for the expression of a subset of genes within Gene set 1 but also significantly contributes to the idiosyncratic gene signature of activated M-MØ. Our results indicate that activation of M-CSF-dependent monocyte-derived macrophages induces a distinctive gene expression profile, which is partially dependent on IL-10, and identifies a gene set potentially helpful for macrophage-centered therapeutic strategies.This work was supported by grants from Ministerio de Economía y Competitividad (SAF2017-83785-R) to M.A.V. and A.L.C., “Ayudas FUNDACIÓN BBVA a equipos de investigación científica SARS-CoV-2 y COVID-19” to M.A.V. and A.L.C., Grant 201619.31 from Fundació La Marató/TV3 to A.L.C., and Red de Investigación en Enfermedades Reumáticas (RIER, RD16/0012/0007), and cofinanced by the European Regional Development Fund “A way to achieve Europe” (ERDF), to A.L.C. V.D.C. was funded by a Formación de Personal Investigador predoctoral fellowship from MINECO (Grant BES-2012-053864).Peer reviewe