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

• Published in: The EMBO journal 2019-06, Vol.38 (11), p.n/a
• Main Authors: Guo, Manman, Härtlova, Anetta, Gierliński, Marek, Prescott, Alan, Castellvi, Josep, Losa, Javier Hernandez, Petersen, Sine K, Wenzel, Ulf A, Dill, Brian D, Emmerich, Christoph H, Ramon Y Cajal, Santiago, Russell, David G, Trost, Matthias
• Format: Article
• Language: English
• Subjects: Animals; Cell activation; Cell and Molecular Biology; Cell Polarity - drug effects; Cell Polarity - genetics; Cell- och molekylärbiologi; Cells, Cultured; Clonal deletion; Debris; EMBO19; EMBO31; EMBO37; Female; Homeostasis; Humans; Immunologi inom det medicinska området; Immunology in the medical area; Inflammation; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Inflammation Mediators - physiology; Interleukin-4 - pharmacology; JNK Mitogen-Activated Protein Kinases - physiology; Kinases; Lipids; Lipolysis; Lipolysis - drug effects; Lipolysis - genetics; Lipoproteins, LDL - pharmacology; Macrophage Activation - drug effects; Macrophage Activation - genetics; macrophage scavenger receptor 1; Macrophages; Macrophages - drug effects; Macrophages - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nutrient transport; Ovarian cancer; Pathogens; Phagocytes; Phagocytosis; Phagocytosis - drug effects; Phagocytosis - genetics; phagosome; Phagosomes; Polysaccharides - pharmacology; Protein Processing, Post-Translational - genetics; Proteolysis; Proteomics; RAW 264.7 Cells; Recruitment; scavenger receptor; Scavenger receptors; Scavenger Receptors, Class A - agonists; Scavenger Receptors, Class A - chemistry; Scavenger Receptors, Class A - genetics; Scavenger Receptors, Class A - metabolism; Scavenging; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; TAK1 protein; Tumors; tumour‐associated macrophages; Ubiquitin; Ubiquitination - genetics
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2018100299

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. Synopsis Macrophage scavenger receptor MSR1 is a key phagocytic receptor for the uptake of lipids and cell debris in macrophages. In IL‐4 activated macrophages MSR1 becomes ubiquitylated, recruits the Tak1/MKK7 kinase complex and signals directly through JNK, which induces pro‐inflammatory cytokine production. Proteomics analysis of phagosomes indicate that alternative activation by IL‐4 enhances phagosomal homeostatic functions in macrophages. Triggering of MSR1 in IL‐4 activated macrophages leads to its ubiquitylation, which recruits the TAK1/MKK7/JNK kinase complex. This leads to pro‐inflammatory signalling, inducing a phenotypic switch of the macrophages. MSR1 ubiquitylation and enhanced JNK signalling is present in human tumour associated macrophages. Graphical Abstract The macrophage scavenger receptor 1 (MSR1) promotes the recruitment of the TAK1/MKK7/JNK signalling complex to the phagosome to drive a macrophage phenotypic shift from an anti‐inflammatory to a pro‐inflammatory one.