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  2. ACT001 suppressing M1 polarization against inflammation via NF-κB and STAT1 signaling pathways alleviates acute lung injury in mice

ACT001 suppressing M1 polarization against inflammation via NF-κB and STAT1 signaling pathways alleviates acute lung injury in mice

  • Int Immunopharmacol. 2022 Sep;110:108944. doi: 10.1016/j.intimp.2022.108944.
Hui Guo 1 Yan Song 2 Fanjian Li 3 Yan Fan 1 Yiman Li 1 Chaonan Zhang 3 Huijie Hou 4 Minmin Shi 1 Zilong Zhao 5 Zhe Chen 6
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, China.
  • 2 Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China.
  • 3 Department of Neurosurgery, Tianjin Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
  • 4 Health Management Centre, Tianjin Medical University General Hospital, Tianjin, China.
  • 5 Department of Neurosurgery, Tianjin Institute of Neurology, Tianjin Medical University General Hospital, Tianjin, China. Electronic address: zilongzhaotianjin@hotmail.com.
  • 6 Department of Geriatrics, Tianjin Geriatrics Institute, Tianjin Medical University General Hospital, Tianjin, China. Electronic address: tjzyycz@sina.com.
Abstract

ACT001 has been shown to exhibit excellent antitumor and anti-fibrosis activities. However, the role of ACT001 in acute lung injury (ALI) and the underlying mechanism remains largely unclear. The present study aimed to investigate the protective effects of ACT001 on ALI and explore the potential mechanisms. Herein, we firstly established the ALI mouse model induced by intratracheal instillation of lipopolysaccharide (LPS). ACT001 treatment significantly alleviated histopathological changes of lung tissues with lower infiltration of pulmonary M1 macrophages in ALI mice. Then, we performed in vitro experiment and found that ACT001 treatment effectively inhibited the M1 phenotype of RAW264.7 and THP-1.. Next, we performed pull-down and mass spectrometry analysis to screen the interacting proteins of ACT001, identifying IKKβ and STAT1 as the critical target proteins of ACT001. And ACT001 treatment significantly suppressed the NF-κB and STAT1 pathways, thereby inhibiting the M1 polarization against inflammation in vivo and in vitro. Finally, we used IMD 0354 (IMD) and Fludarabine (Flud) to specifically block the activity of IKKβ and STAT1, and stimulated macrophages through IKKβ and STAT1 overexpression. Our data clearly showed that ACT001-induced decrease of the M1 polarization was blocked by IMD and Flud treatment, and reversed by IKKβ and STAT1 overexpression in RAW264.7 cells. In conclusion, we discovered that ACT001 significantly alleviates inflammation and limits M1 phenotype of pulmonary macrophages via suppressing NF-κB and STAT1 signaling pathways, providing new insights for the development of drugs to treat ALI/ARDS.

Keywords

ACT001; Acute lung injury; Macrophage polarization; NF-κB; STAT1.

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