Gene-selective transcription promotes the inhibition of tissue reparative macrophages by TNF
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Life Science Alliance |
Volume | 5 |
Issue number | 4 |
ISSN | 2575-1077 |
DOIs | |
Publication status | Published - Apr 2022 |
Externally published | Yes |
Bibliographical note
© 2022 Dichtl et al.
- Animals, Cells, Cultured, Cytokines/metabolism, Female, Macrophage Activation/drug effects, Macrophages/drug effects, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction/drug effects, Transcription, Genetic/drug effects, Tumor Necrosis Factor Inhibitors/pharmacology, Tumor Necrosis Factor-alpha/metabolism
Research areas
ID: 303114298