Keap1 Deficiency Promotes Macrophage M2 Polarization and Protects β Cells

Abstract

Background Progressive pancreatic β‐cell injury is a core feature of Type 2 diabetes mellitus (T2DM). Imbalance between macrophage M1 and M2 polarization, driven by chronic inflammation, is a key contributor to this injury. The Keap1‐Nrf2‐ARE pathway regulates macrophage polarization and inflammatory responses, but whether it affects pancreatic β‐cell survival through macrophages is unknown. Methods We generated a Keap1‐knockout THP‐1 line using CRISPR‐Cas9, differentiated the cells into M0 macrophages with PMA, polarized them toward M2 with IL‐4/IL‐13, and cocultured them with MIN6 cells injured by LPS. Results Keap1 knockout increased M2 polarization efficiency and reduced the nuclear‐to‐cytoplasmic ratio of NF‐κB p65, with lower IL‐1β and TNF‐α mRNA expression. After coculture with LPS‐injured MIN6 cells, the Keap1‐KO‐M2 group showed higher MIN6 viability and less apoptosis. The antiapoptotic protein Bcl‐2 rose, whereas the proapoptotic factors Bax and cleaved‐caspase3 declined; MDA content fell, whereas HO‐1 and SOD levels climbed. Conclusion These findings indicate that Keap1 deficiency attenuates LPS‐induced pancreatic β‐cell injury by increasing macrophage M2 polarization efficiency and expanding the M2 population.