Summary
Alternatively activated M2 macrophages (AAMs) play an important role in maintenance of tissue homeostasis by scavenging dead cells and cell debris via phagocytosis. An essential step in this process is phagosomal maturation. Using highresolution LC-MS/MS, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. One of the most intriguing insights was the recruitment of the TAK1/MKK7/JNK signalling complex to the phagosomes of IL-4 activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). MSR1 activation induced JNK signalling, thereby facilitating macrophage polarization towards an M1 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 in a K63-polyubiquitylation-dependent manner and provide evidence for the receptor’s involvement in macrophage polarization.
- ABBREVIATIONS
- BMDM
- bone marrow-derived macrophages
- BSA
- bovine serum albumin
- ER
- endoplasmic reticulum
- FDR
- false discovery rate
- GO
- Gene ontology
- IFN
- interferon
- IL-4
- interleukin-4
- LC
- liquid chromatography
- LPS
- lipopolysaccharide
- MS
- mass spectrometry
- oxLDL
- oxidised low-density lipoprotein
- ROS
- reactive oxygen species
- TAMs
- tumour-associated macrophages