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

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.

The effects of pinoresinol on cholinergic dysfunction-induced memory impairments and synaptic plasticity in mice.

Dementia is a category of brain diseases that cause a decrease in cognitive functions. Alzheimer's disease (AD) is the most frequently mentioned neurodegenerative disease showing dementia. Although many useful drugs for dementia were developed, we still need better and safer drugs. Here, we tested pinoresinol, a lignan found in sesame seed and olive oil, whether it could be a candidate for this purpose. Pinoresinol (25 mg/kg, p.o.) ameliorated memory impairment in dementia model induced by cholinergic blockade in the passive avoidance test in a dose-dependent manner. Moreover, pinoresinol (50 µM) facilitated induction of hippocampal long-term potentiation, a cellular model of learning and memory. Pinoresinol blocked acetylcholinesterase (AchE), an acetylcholine-degrading enzyme, activity in a concentration-dependent manner. Moreover, pinoresinol (50 µM) facilitated calcium influx into neuro2a cell. These results suggest that pinoresinol improves memory impairment and facilitates hippocampal LTP induction and these results might be related to the effect of pinoresinol on AChE and calcium influx.