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

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.

The active fraction of Garcinia yunnanensis suppresses the progression of colorectal carcinoma by interfering with tumorassociated macrophage‐associated M2 macrophage polarization in vivo and in vitro

“…Similar to Flow cytometric analysis, YTE‐17 significantly restrained M2 marker (Arg‐1) and enhanced M1 marker (iNOS) expression, respectively (Figure 3B up). Extensive evidence suggests that the phosphorylation of some known signaling pathways, including ERK, JNK, and STAT3, is markedly enhanced by tumor supernatant stimulation in RAW264.7 cells 34-36 . To further explore the potential mechanism of YTE‐17, we used in vitro models to identify the pathway that could be regulated as YTE‐17 inhibits M2 macrophage polarization.…”

Identification of Novel Targets of Knee Osteoarthritis Shared by Cartilage and Synovial Tissue

“…Besides, MSR1 is a multifunctional receptor expressed primarily on cells of the myeloid lineage [ 47 ]. It positively regulates the activation of macrophages and thus promoting the inflammation [ 48 ]. The genetic deficiency of Msr1 decreased the incidence and severity of autoimmune arthritis in the K/BxN T cell receptor (TCR) transgenic mouse model [ 47 ].…”

Nogo-A is critical for pro-inflammatory gene regulation in myocytes and macrophages

“…IL-1β is also a vital pro-in ammatory factor that is produced by M1 macrophages and promotes activation of the NF-κB pathway [58,59]. In contrast, anti-in ammatory macrophages, which are also known as alternativeactivated macrophages, express higher levels of anti-in ammatory mediators, such as IL-10, CD206, and arginase-1 [8,60]. M2 macrophages inhibit pro-in ammatory mediators as well as their responses and promote angiogenesis and the resolution of in ammation, which are key aspects of tissue repair [61,62].…”