PLD1 and PLD2 differentially regulate the balance of macrophage polarization in inflammation and tissue injury

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Phospholipase D (PLD) isoforms PLD1 and PLD2 are key signaling nodes.
• Their specific functions in cellular processes, particularly macrophage polarization, are not fully understood.

Purpose of the Study:

• To elucidate the isoform-specific functions of PLD1 and PLD2 in regulating macrophage polarization.
• To investigate the signaling pathways and receptor interactions governing these functions.

Main Methods:

• Utilized toll-like receptor 4 (TLR4) and interleukin 4 receptor (IL-4R) signaling models.
• Examined interactions with MyD88 and JAK3 signaling pathways.
• Employed genetic (PLD1/PLD2 ablation) and pharmacological approaches.
• Assessed macrophage polarization (M1/M2) and inflammatory responses in injury models.

Main Results:

• PLD1 selectively couples with TLR4/MyD88 axis to promote M1 polarization.
• PLD2 selectively couples with IL-4R/JAK3 signaling to promote M2 polarization.
• Targeting PLD1 protected against LPS-induced sepsis and tissue injury by shifting towards M2 polarization.
• PLD2 deficiency exacerbated disease by promoting M1 polarization.
• PLD1 influenced regulatory T cell recruitment and macrophage phenotype.

Conclusions:

• PLD1 and PLD2 play indispensable, opposing roles in M1 and M2 macrophage polarization, respectively.
• Isoform-specific signaling events dictate macrophage fate.
• PLD isoforms represent potential therapeutic targets for modulating macrophage responses in inflammatory diseases.