PMID- 34644617 OWN - NLM STAT- MEDLINE DCOM- 20211123 LR - 20220531 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 176 DP - 2021 Nov 20 TI - Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury. PG - 378-391 LID - S0891-5849(21)00755-3 [pii] LID - 10.1016/j.freeradbiomed.2021.10.007 [doi] AB - 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 alpha (TNF-alpha), interleukin (IL)-1beta, 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. CI - Copyright (c) 2021 Elsevier Inc. All rights reserved. FAU - Dhar, Rana AU - Dhar R AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Rana, Mohammad Nasiruddin AU - Rana MN AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Zhang, Lejun AU - Zhang L AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Li, Yajun AU - Li Y AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Li, Ning AU - Li N AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Hu, Zhengqiang AU - Hu Z AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Yan, Chungunag AU - Yan C AD - Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing 210009, China. FAU - Wang, Xuefeng AU - Wang X AD - Department of Pharmacy, Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310005, China. FAU - Zheng, Xuyang AU - Zheng X AD - Department of Pediatrics, The Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China. FAU - Liu, Hongyun AU - Liu H AD - Institute of Dairy Science, MoE Key Laboratory of Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. FAU - Cui, Huashun AU - Cui H AD - Department of Acupuncture and Moxibustion, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China. Electronic address: cuihuashun@shutcm.edu.cn. FAU - Li, Zigang AU - Li Z AD - Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, China. Electronic address: lizigang@zju.edu.cn. FAU - Tang, Huifang AU - Tang H AD - Department of Pharmacology, Zhejiang Respiratory Drugs Research Laboratory, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China. Electronic address: tanghuifang@zju.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211010 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4) RN - EC 3.1.4.17 (PDE4B protein, mouse) SB - IM MH - *Acute Lung Injury/chemically induced/genetics MH - Animals MH - Cyclic Nucleotide Phosphodiesterases, Type 4/genetics MH - Feedback MH - *Inflammasomes/genetics MH - Interleukin-1beta MH - Lipopolysaccharides/toxicity MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred NOD MH - NF-E2-Related Factor 2/genetics MH - NLR Family, Pyrin Domain-Containing 3 Protein/genetics OTO - NOTNLM OT - Acute lung injury OT - Inflammasome OT - NLRP3 OT - Nrf2 OT - PDE4B EDAT- 2021/10/14 06:00 MHDA- 2021/11/24 06:00 CRDT- 2021/10/13 20:08 PHST- 2021/09/07 00:00 [received] PHST- 2021/10/03 00:00 [revised] PHST- 2021/10/08 00:00 [accepted] PHST- 2021/10/14 06:00 [pubmed] PHST- 2021/11/24 06:00 [medline] PHST- 2021/10/13 20:08 [entrez] AID - S0891-5849(21)00755-3 [pii] AID - 10.1016/j.freeradbiomed.2021.10.007 [doi] PST - ppublish SO - Free Radic Biol Med. 2021 Nov 20;176:378-391. doi: 10.1016/j.freeradbiomed.2021.10.007. Epub 2021 Oct 10.