Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages

Manman Guo, Anetta Härtlova (Lead / Corresponding author), Marek Gierlinski, Alan Prescott, Josep Castellvi, Javier Hernandez Losa, Sine K. Petersen, Ulf A. Wenzel, Brian D. Dill, Christoph H. Emmerich, Santiago Ramon Y Cajal, David G. Russell, Matthias Trost (Lead / Corresponding author)

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Abstract

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo. Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization.

Original languageEnglish
Article numbere100299
Pages (from-to)1-15
Number of pages15
JournalEMBO Journal
Volume38
Issue number11
Early online date26 Apr 2019
DOIs
Publication statusPublished - 3 Jun 2019

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Keywords

  • macrophage scavenger receptor 1
  • phagosome
  • proteomics
  • scavenger receptor
  • tumour-associated macrophages

Cite this

Guo, M., Härtlova, A., Gierlinski, M., Prescott, A., Castellvi, J., Hernandez Losa, J., Petersen, S. K., Wenzel, U. A., Dill, B. D., Emmerich, C. H., Ramon Y Cajal, S., Russell, D. G., & Trost, M. (2019). Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages. EMBO Journal, 38(11), 1-15. [e100299]. https://doi.org/10.15252/embj.2018100299