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.
Subject(s)
Inflammation , Interleukin-4/pharmacology , JNK Mitogen-Activated Protein Kinases/physiology , Macrophage Activation , Scavenger Receptors, Class A/agonists , Scavenger Receptors, Class A/genetics , Animals , Cell Polarity/drug effects , Cell Polarity/genetics , Cells, Cultured , Female , Humans , Inflammation/chemically induced , Inflammation/genetics , Inflammation/metabolism , Inflammation Mediators/physiology , Lipolysis/drug effects , Lipolysis/genetics , Lipoproteins, LDL/pharmacology , Macrophage Activation/drug effects , Macrophage Activation/genetics , Macrophages/drug effects , Macrophages/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Phagocytosis/drug effects , Phagocytosis/genetics , Polysaccharides/pharmacology , Protein Processing, Post-Translational/genetics , RAW 264.7 Cells , Scavenger Receptors, Class A/chemistry , Scavenger Receptors, Class A/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Ubiquitination/geneticsABSTRACT
Organisms adapt their metabolism and growth to the availability of nutrients and oxygen, which are essential for development, yet the mechanisms by which this adaptation occurs are not fully understood. Here we describe an RNAi-based body-size screen in Drosophila to identify such mechanisms. Among the strongest hits is the fibroblast growth factor receptor homolog breathless necessary for proper development of the tracheal airway system. Breathless deficiency results in tissue hypoxia, sensed primarily in this context by the fat tissue through HIF-1a prolyl hydroxylase (Hph). The fat relays its hypoxic status through release of one or more HIF-1a-dependent humoral factors that inhibit insulin secretion from the brain, thereby restricting systemic growth. Independently of HIF-1a, Hph is also required for nutrient-dependent Target-of-rapamycin (Tor) activation. Our findings show that the fat tissue acts as the primary sensor of nutrient and oxygen levels, directing adaptation of organismal metabolism and growth to environmental conditions.