The CNC-bZIP transcription factor Nrf2 controls expression of matrix metalloproteases in murine macrophages

TY - JOUR

T1 - The CNC-bZIP transcription factor Nrf2 controls expression of matrix metalloproteases in murine macrophages

AU - Ang, Abel

AU - Dayalan Naidu, Sharadha

AU - Read, Oliver J

AU - Bian, Pingting

AU - Sandilands, Aileen

AU - Kisielewski, Dot

AU - Arthur, J Simon C

AU - Kendall, Timothy J.

AU - Campana, Lara

AU - Forbes, Stuart J

AU - Henderson, Neil C

AU - Honda, Tadashi

AU - Pi, Jingbo

AU - Suzuki, Takafumi

AU - Yamamoto, Masayuki

AU - Dinkova-Kostova, Albena

AU - Hayes, John

N1 - Publisher Copyright: © The Author(s) 2026. Published by Oxford University Press on behalf of Society for Leukocyte Biology.

PY - 2026/3/4

Y1 - 2026/3/4

N2 - Liver fibrosis is a chronic condition that often leads to organ failure. Currently, no effective treatment exists for advanced liver fibrosis. De-repression of the transcription factor Nrf2, by inhibition of the ubiquitin ligase substrate adaptor Keap1, is a promising strategy to treat liver fibrosis because Nrf2 augments cytoprotection and blunts the profibrotic TGF-β pathway. Herein, Nrf2 is reported to control matrix metalloproteinase (MMP) expression during chronic liver injury, and more specifically in macrophages, which play a key role in the resolution of fibrosis. We found impaired expression of Mmp8, Mmp9, Mmp12, and Mmp14 in the livers of Nrf2-knockout (Nrf2-ko) mice compared to wild-type (WT) mice, both basally and following CCl 4 damage. Investigation of bone-marrow-derived macrophages (BMDMs) revealed profoundly impaired expression of Mmp8 and Mmp12 in Nrf2-ko BMDMs and a concomitant hyper-expression in Keap1-knockdown (Keap1-kd) BMDMs, which were corroborated by siRNA knockdown of Nrf2 and macrophage-specific conditional knockout of Nrf2. This trend was observed under basal conditions and post-efferocytosis. Total MMP activity was also found to be highest in the conditioned medium of Keap1-kd post-efferocytosis BMDMs. ChIP-seq revealed Nrf2-binding sites upstream of Mmp12, which also showed the strongest expression response to Nrf2. Lastly, through pharmacological de-repression of Nrf2, using TBE-31 to inhibit Keap1, upregulation of MMP expression was observed in BMDMs and livers of mice following acute liver injury. In conclusion, Nrf2 has been shown to be a regulator of MMP expression and activity in stimulated macrophages, which reveals a new mechanism by which Nrf2 regulates macrophage function.

AB - Liver fibrosis is a chronic condition that often leads to organ failure. Currently, no effective treatment exists for advanced liver fibrosis. De-repression of the transcription factor Nrf2, by inhibition of the ubiquitin ligase substrate adaptor Keap1, is a promising strategy to treat liver fibrosis because Nrf2 augments cytoprotection and blunts the profibrotic TGF-β pathway. Herein, Nrf2 is reported to control matrix metalloproteinase (MMP) expression during chronic liver injury, and more specifically in macrophages, which play a key role in the resolution of fibrosis. We found impaired expression of Mmp8, Mmp9, Mmp12, and Mmp14 in the livers of Nrf2-knockout (Nrf2-ko) mice compared to wild-type (WT) mice, both basally and following CCl 4 damage. Investigation of bone-marrow-derived macrophages (BMDMs) revealed profoundly impaired expression of Mmp8 and Mmp12 in Nrf2-ko BMDMs and a concomitant hyper-expression in Keap1-knockdown (Keap1-kd) BMDMs, which were corroborated by siRNA knockdown of Nrf2 and macrophage-specific conditional knockout of Nrf2. This trend was observed under basal conditions and post-efferocytosis. Total MMP activity was also found to be highest in the conditioned medium of Keap1-kd post-efferocytosis BMDMs. ChIP-seq revealed Nrf2-binding sites upstream of Mmp12, which also showed the strongest expression response to Nrf2. Lastly, through pharmacological de-repression of Nrf2, using TBE-31 to inhibit Keap1, upregulation of MMP expression was observed in BMDMs and livers of mice following acute liver injury. In conclusion, Nrf2 has been shown to be a regulator of MMP expression and activity in stimulated macrophages, which reveals a new mechanism by which Nrf2 regulates macrophage function.

KW - Nrf2

KW - efferocytosis

KW - fibrosis

KW - macrophage

KW - matrix metalloproteinase

U2 - 10.1093/jleuko/qiag021

DO - 10.1093/jleuko/qiag021

M3 - Article

SN - 0741-5400

VL - 118

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

IS - 3

M1 - qiag021

ER -