Journal of diabetes research · 2026
Keap1 Deficiency Promotes Macrophage M2 Polarization and Protects β Cells.
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Huang Baoliang, Mou Lunpan, Huang Xiaoyan, Su Siyu, Hong Zhenzhen, Zhang Yi
Аннотация
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.
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.