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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Alternatively activated M2 macrophages are crucial for tissue homeostasis and debris clearance via phagocytosis.
• Interleukin-4 (IL-4) drives alternative activation, modulating macrophage functions.
• Understanding the molecular mechanisms of M2 macrophage polarization is key to tissue repair and inflammatory processes.

Purpose of the Study:

• To investigate how IL-4-driven alternative activation affects the phagosomal proteome and macrophage function.
• To identify key signaling pathways and receptors involved in M2 macrophage polarization.
• To explore the role of macrophage scavenger receptor 1 (MSR1) in IL-4-mediated signaling.

Main Methods:

• Proteomics analysis of phagosomes from IL-4-activated macrophages.
• Investigation of signaling complex recruitment to phagosomes.
• Assessment of MSR1 polyubiquitylation and its effect on JNK activation.
• Macrophage deletion studies and JNK inhibition experiments.
• Analysis of MSR1 polyubiquitylation and JNK signaling in human ovarian cancer tissue.

Main Results:

• Alternative activation enhances macrophage homeostatic functions including proteolysis, lipolysis, and nutrient transport.
• Enhanced recruitment of the TAK1/MKK7/JNK signaling complex to phagosomes was observed.
• K63 polyubiquitylation of MSR1 mediated the recruitment of this complex.
• MSR1 triggering led to increased JNK activation, promoting a switch from anti-inflammatory to pro-inflammatory phenotype.
• This phenotypic switch was abrogated by MSR1 deletion or JNK inhibition.
• MSR1 K63 polyubiquitylation and JNK activation correlated in human ovarian cancer tissues.

Conclusions:

• MSR1 signals through JNK via K63 polyubiquitylation, influencing macrophage polarization.
• MSR1 plays a significant role in modulating macrophage phenotype, potentially shifting from a homeostatic to a pro-inflammatory state.
• The identified MSR1-JNK pathway may be relevant in inflammatory conditions like ovarian cancer.