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

Life Sci Alliance. 2022 Jan 13;5(4):e202101315. doi: 10.26508/lsa.202101315. Print 2022 Apr.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Female
  • Macrophage Activation / drug effects
  • Macrophages* / drug effects
  • Macrophages* / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcription, Genetic* / drug effects
  • Transcription, Genetic* / genetics
  • Tumor Necrosis Factor Inhibitors / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism*


  • Cytokines
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factor-alpha