PMID- 36516721 OWN - NLM STAT- MEDLINE DCOM- 20230117 LR - 20230705 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 59 DP - 2023 Feb TI - Loss of selenoprotein W in murine macrophages alters the hierarchy of selenoprotein expression, redox tone, and mitochondrial functions during inflammation. PG - 102571 LID - S2213-2317(22)00343-3 [pii] LID - 10.1016/j.redox.2022.102571 [doi] LID - 102571 AB - Macrophages play a pivotal role in mediating inflammation and subsequent resolution of inflammation. The availability of selenium as a micronutrient and the subsequent biosynthesis of selenoproteins, containing the 21(st) amino acid selenocysteine (Sec), are important for the physiological functions of macrophages. Selenoproteins regulate the redox tone in macrophages during inflammation, the early onset of which involves oxidative burst of reactive oxygen and nitrogen species. SELENOW is a highly expressed selenoprotein in bone marrow-derived macrophages (BMDMs). Beyond its described general role as a thiol and peroxide reductase and as an interacting partner for 14-3-3 proteins, its cellular functions, particularly in macrophages, remain largely unknown. In this study, we utilized Selenow knock-out (KO) murine bone marrow-derived macrophages (BMDMs) to address the role of SELENOW in inflammation following stimulation with bacterial endotoxin lipopolysaccharide (LPS). RNAseq-based temporal analyses of expression of selenoproteins and the Sec incorporation machinery genes suggested no major differences in the selenium utilization pathway in the Selenow KO BMDMs compared to their wild-type counterparts. However, selective enrichment of oxidative stress-related selenoproteins and increased ROS in Selenow(-/-) BMDMs indicated anomalies in redox homeostasis associated with hierarchical expression of selenoproteins. Selenow(-/-) BMDMs also exhibited reduced expression of arginase-1, a key enzyme associated with anti-inflammatory (M2) phenotype necessary to resolve inflammation, along with a significant decrease in efferocytosis of neutrophils that triggers pathways of resolution. Parallel targeted metabolomics analysis also confirmed an impairment in arginine metabolism in Selenow(-/-) BMDMs. Furthermore, Selenow(-/-) BMDMs lacked the ability to enhance characteristic glycolytic metabolism during inflammation. Instead, these macrophages atypically relied on oxidative phosphorylation for energy production when glucose was used as an energy source. These findings suggest that SELENOW expression in macrophages may have important implications on cellular redox processes and bioenergetics during inflammation and its resolution. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Misra, Sougat AU - Misra S AD - Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Lee, Tai-Jung AU - Lee TJ AD - Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Sebastian, Aswathy AU - Sebastian A AD - Bioinformatics Core, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - McGuigan, John AU - McGuigan J AD - Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Liao, Chang AU - Liao C AD - Department of Medicine- Infectious Diseases, University of California, San Francisco, CA, 94143, USA. FAU - Koo, Imhoi AU - Koo I AD - Metabolomics Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Patterson, Andrew D AU - Patterson AD AD - Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, 16802, USA; Metabolomics Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Rossi, Randall M AU - Rossi RM AD - Transgenic Mouse Core Facility, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Hall, Molly A AU - Hall MA AD - Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Albert, Istvan AU - Albert I AD - Bioinformatics Core, Huck Institute of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA. FAU - Prabhu, K Sandeep AU - Prabhu KS AD - Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA, 16802, USA. Electronic address: ksp4@psu.edu. LA - eng GR - R01 CA239256/CA/NCI NIH HHS/United States GR - R01 DK077152/DK/NIDDK NIH HHS/United States GR - R01 DK119865/DK/NIDDK NIH HHS/United States GR - R56 DK077152/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20221208 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (Selenoprotein W) RN - H6241UJ22B (Selenium) RN - 0 (Selenoproteins) SB - IM MH - Mice MH - Animals MH - *Selenoprotein W/genetics/metabolism MH - *Selenium/metabolism MH - Selenoproteins/genetics/metabolism MH - Macrophages/metabolism MH - Oxidation-Reduction MH - Inflammation/genetics PMC - PMC9762199 OTO - NOTNLM OT - Arginase OT - Energy metabolism OT - Glycolysis OT - Krebs cycle OT - Metabolism OT - Mitochondrial respiration OT - Reactive oxygen species OT - Resolution OT - Sik2 COIS- Conflict-of-interest statement All the authors have read the manuscript and approved its final version before the submission. None of the authors have any potential conflict-of-interests to declare. EDAT- 2022/12/15 06:00 MHDA- 2023/01/18 06:00 PMCR- 2022/12/08 CRDT- 2022/12/14 18:32 PHST- 2022/11/20 00:00 [received] PHST- 2022/12/04 00:00 [accepted] PHST- 2022/12/15 06:00 [pubmed] PHST- 2023/01/18 06:00 [medline] PHST- 2022/12/14 18:32 [entrez] PHST- 2022/12/08 00:00 [pmc-release] AID - S2213-2317(22)00343-3 [pii] AID - 102571 [pii] AID - 10.1016/j.redox.2022.102571 [doi] PST - ppublish SO - Redox Biol. 2023 Feb;59:102571. doi: 10.1016/j.redox.2022.102571. Epub 2022 Dec 8.