2. Academic Validation
  3. Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury

Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury

  • Free Radic Biol Med. 2021 Nov 20;176:378-391. doi: 10.1016/j.freeradbiomed.2021.10.007.
Rana Dhar 1,  Mohammad Nasiruddin Rana 1,  Lejun Zhang 1,  Yajun Li 1,  Ning Li 1,  Zhengqiang Hu 1,  Chungunag Yan 2,  Xuefeng Wang 3,  Xuyang Zheng 4,  Hongyun Liu 5,  Huashun Cui 6,  Zigang Li 7,  Huifang Tang 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing 210009, China.
  • 3 Department of Pharmacy, Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China.
  • 4 Department of Pediatrics, The Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
  • 5 Institute of Dairy Science, MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 6 Department of Acupuncture and Moxibustion, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China. Electronic address: [email protected].
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, China. Electronic address: [email protected].
  • 8 Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: [email protected].
PMID: 34644617 DOI: 10.1016/j.freeradbiomed.2021.10.007
Abstract

Acute lung injury (ALI) is associated with overproduction of inflammatory mediators in lung tissue. Previous studies have revealed that inflammation induces activation of phosphodiesterase 4B (PDE4B) accompanied by the production of inflammatory mediators, but the detailed mechanism remains unclear. Here, we focused on the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome complexes to study the crosstalk between PDE4B and NF-E2-related factor 2 (Nrf2). We used global knockout PDE4B or Nrf2 mice to prepare LPS induced acute lung injury model by intratracheally administration, and LPS primed bone marrow-derived macrophages (BMDMs), following overexpression of PDE4B or Nrf2, luciferase activity analysis, and chIP-qPCR analyses. We found that deficiency of PDE4B could potently attenuate the lung histopathological changes, suppress the secretion of pro-inflammatory mediators such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6, IL-18, and cleaved Caspase-1, 8, and GSDMD accompanied with defective activation of the ROS/Nrf2/NLRP3. Meanwhile deficiency of Nrf2 showed the similar results. Furtherly, overexpression by PDE4B or Nrf2 plasmid transfection in MH-S cells could enhance the Nrf2 or PDE4B expression. Luciferase analysis suggested that Nrf2 activated PDE4B promoter activity, while PDE4B could increase Nrf2 substrate ARE activity in MH-S cells in dose dependent manners. ChIP-qPCR analyses showed that Nrf2 bound to the PDE4B promoter region at ̴ 1532 to ̴1199 position in macrophages. Altogether, deficiency of PDE4B inhibit the inflammasome activation and Pyroptosis in LPS stimulated lung injury model and macrophages by regulating ROS/Nrf2/NLRP3 activation. The study provides new insight that PDE4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2.

Keywords

Acute lung injury; Inflammasome; NLRP3; Nrf2; PDE4B.

Figures
Products