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 Pld1^LyzCre macrophages. We reveal a previously uncharacterized role of PLD isoforms in macrophage polarization, signifying potential pharmacological interventions for macrophage modulation.

中文翻译：

---

PLD1和PLD2在炎症和组织损伤中差异调节巨噬细胞极化的平衡

磷脂酶 D (PLD) 同种型 PLD1 和 PLD2 作为主要节点，不同的信号通路汇聚于此。然而，它们的亚型特异性功能仍不清楚。我们发现 PLD1 和 PLD2 选择性地与 Toll 样受体 4 (TLR4) 和白介素 4 受体 (IL-4R) 偶联，并通过 LPS-MyD88 轴和 IL-4-JAK3 信号传导差异调节 M1 和 M2 的巨噬细胞极化，分别。脂多糖 (LPS) 增强了 TLR4 或 MyD88 与 PLD1 的相互作用；IL-4 诱导 IL-4R 或 JAK3 与 PLD2 结合，表明同工酶特异性信号事件。PLD1和PLD2分别是M1极化和M2极化必不可少的。PLD1 的遗传和药理学靶向通过促进向 M2 的转变赋予对 LPS 诱导的败血症、心脏毒素诱导的肌肉损伤和皮肤损伤的保护；PLD2 消融通过促进向 M1 的转变加剧了疾病的严重程度。增强型 Foxp3⁺调节性 T 细胞募集也影响Pld1 ^LyzCre巨噬细胞的抗炎表型。我们揭示了 PLD 同种型在巨噬细胞极化中的先前未表征的作用，这意味着巨噬细胞调节的潜在药理学干预。