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

• Manman Guo ^[1] ; Anetta Härtlova ^[1] ; Marek Gierliński ^[2] ; Alan Prescott ^[2] ; Josep Castellvi ^[5] ; Javier Hernandez Losa ^[6] ; Sine K Petersen ^[3] ; Ulf A Wenzel ^[3] ; Brian D Dill ^[1] ; Christoph H Emmerich ^[1] ; Santiago Ramon Y Cajal ^[6] ; David G Russell ^[4] ; Matthias Trost ^[1]
  1. [1] MRC Protein Phosphorylation and Ubiquitylation Unit

     MRC Protein Phosphorylation and Ubiquitylation Unit

     Reino Unido

     
  2. [2] University of Dundee

     University of Dundee

     Reino Unido

     
  3. [3] University of Gothenburg

     University of Gothenburg

     Suecia

     
  4. [4] Cornell University

     Cornell University

     City of Ithaca, Estados Unidos

     
  5. [5] 7 Department of Pathology Hospital Universitario Vall d'Hebron Barcelona Spain
  6. [6] 7 Department of Pathology Hospital Universitario Vall d'Hebron Barcelona Spain; 8 Spanish Biomedical Research Network Centre in Oncology (CIBERONC) Barcelona Spain

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 38, Nº. 11, 2019
• Idioma: inglés
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• Resumen

  • 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.