Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF

Stefanie Dichtl, David E. Sanin, Carolin K. Koss, Sebastian Willenborg, Andreas Petzold, Maria C. Tanzer, Andreas Dahl, Agnieszka M. Kabat, Laura Lindenthal, Leonie Zeitler, Sabrina Satzinger, Alexander Strasser, Matthias Mann, Axel Roers, Sabine A. Eming, Karim C. El Kasmi, Edward J. Pearce, Peter J. Murray

Research output: Contribution to journalArticlepeer-review

Abstract

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 panM2 inhibitor.

Original languageEnglish (US)
Article numbere202101315
JournalLife science alliance
Volume5
Issue number4
DOIs
StatePublished - Apr 2022

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Health, Toxicology and Mutagenesis
  • Plant Science
  • Ecology

Fingerprint

Dive into the research topics of 'Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF'. Together they form a unique fingerprint.

Cite this