RT Journal Article SR Electronic T1 Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202101315 DO 10.26508/lsa.202101315 VO 5 IS 4 A1 Stefanie Dichtl A1 David E Sanin A1 Carolin K Koss A1 Sebastian Willenborg A1 Andreas Petzold A1 Maria C Tanzer A1 Andreas Dahl A1 Agnieszka M Kabat A1 Laura Lindenthal A1 Leonie Zeitler A1 Sabrina Satzinger A1 Alexander Strasser A1 Matthias Mann A1 Axel Roers A1 Sabine A Eming A1 Karim C El Kasmi A1 Edward J Pearce A1 Peter J Murray YR 2022 UL https://www.life-science-alliance.org/content/5/4/e202101315.abstract AB Anti-TNF therapies are a core anti-inflammatory approach for chronic diseases such as rheumatoid arthritis and Crohn’s Disease. Previously, we and others found that TNF blocks the emergence and function of alternative-activated or M2 macrophages involved in wound healing and tissue-reparative functions. Conceivably, anti-TNF drugs could mediate their protective effects in part by an altered balance of macrophage activity. To understand the mechanistic basis of how TNF regulates tissue-reparative macrophages, we used RNAseq, scRNAseq, ATACseq, time-resolved phospho-proteomics, gene-specific approaches, metabolic analysis, and signaling pathway deconvolution. We found that TNF controls tissue-reparative macrophage gene expression in a highly gene-specific way, dependent on JNK signaling via the type 1 TNF receptor on specific populations of alternative-activated macrophages. We further determined that JNK signaling has a profound and broad effect on activated macrophage gene expression. Our findings suggest that TNF’s anti-M2 effects evolved to specifically modulate components of tissue and reparative M2 macrophages and TNF is therefore a context-specific modulator of M2 macrophages rather than a pan-M2 inhibitor.