PLD1 and PLD2 differentially regulate the balance of macrophage polarization in inflammation and tissue injury.
Won Chan HwangSeol Hwa SeoMinju KangRae Hee KangGilbert Di PaoloKang-Yell ChoiDo Sik MinPublished in: Journal of cellular physiology (2020)
Phospholipase D (PLD) isoforms PLD1 and PLD2 serve as the primary nodes where diverse signaling pathways converge. However, their isoform-specific functions remain unclear. We showed that PLD1 and PLD2 selectively couple to toll-like receptor 4 (TLR4) and interleukin 4 receptor (IL-4R) and differentially regulate macrophage polarization of M1 and M2 via the LPS-MyD88 axis and the IL-4-JAK3 signaling, respectively. Lipopolysaccharide (LPS) enhanced TLR4 or MyD88 interaction with PLD1; IL-4 induced IL-4R or JAK3 association with PLD2, indicating isozyme-specific signaling events. PLD1 and PLD2 are indispensable for M1 polarization and M2 polarization, respectively. Genetic and pharmacological targeting of PLD1 conferred protection against LPS-induced sepsis, cardiotoxin-induced muscle injury, and skin injury by promoting the shift toward M2; PLD2 ablation intensified disease severity by promoting the shift toward M1. Enhanced Foxp3+ regulatory T cell recruitment also influenced the anti-inflammatory phenotype of Pld1LyzCre macrophages. We reveal a previously uncharacterized role of PLD isoforms in macrophage polarization, signifying potential pharmacological interventions for macrophage modulation.
Keyphrases
- toll like receptor
- inflammatory response
- lps induced
- nuclear factor
- physical activity
- oxidative stress
- signaling pathway
- gene expression
- acute kidney injury
- regulatory t cells
- high glucose
- cell proliferation
- genome wide
- single cell
- sentinel lymph node
- rectal cancer
- atrial fibrillation
- diabetic rats
- binding protein
- induced apoptosis