Notch signaling increases PPARγ protein stability and enhances lipid uptake through AKT in IL‐4‐stimulated THP‐1 and primary human macrophages

Notch signaling and nuclear receptor PPARγ are involved in macrophage polarization, but cross talk between them has not been reported in macrophages. In this study, the effect of Notch signaling on PPARγ in IL‐4‐stimulated human macrophages (M(IL‐4)) was investigated using THP‐1‐derived macrophages and human monocyte‐derived macrophages as models. Human M(IL‐4) increased the expression of JAGGED1 and activated Notch signaling. Overexpression of Notch1 intracellular domain (NIC1) increased PPARγ expression, while inhibiting Notch signaling decreased PPARγ levels in M(IL‐4). NIC1 overexpression in THP‐1‐derived macrophages increased PPARγ protein stability by delaying its proteasome‐mediated degradation, but did not affect its mRNA. Phosphorylation of AKT was enhanced in NIC1‐overexpressing cells, and a specific AKT inhibitor reduced the level of PPARγ. NIC1‐overexpressing THP‐1 cells exhibited increased CD36 levels via activation of PPARγ, resulting in enhanced intracellular lipid accumulation. In summary, this study provides evidence linking Notch signaling and PPARγ via AKT in M(IL‐4). Notch signaling is known to regulate activation of pro‐inflammatory macrophages. Here, we report that IL‐4‐stimulated human macrophages (M(IL‐4)) promptly activate Notch signaling via JAGGED1. This activation is accompanied by increased PPARγ, a key transcription factor for M(IL‐4). Cross talk between Notch signaling and AKT/ERK pathways was observed. Interfering with Notch signaling affects PPARγ level and its biological functions.