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Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy

Fabry disease (FD) is a rare X‐linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α‐galactosidase. Gb3 deposits activate immune‐mediated systemic inflammation, ultimately leading to life‐threatening consequence...

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Autores principales: Fu, Li, Wasiak, Sylwia, Tsujikawa, Laura M., Rakai, Brooke D., Stotz, Stephanie C., Wong, Norman C. W., Johansson, Jan O., Sweeney, Michael, Mohan, Connie M., Khan, Aneal, Kulikowski, Ewelina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007222/
https://www.ncbi.nlm.nih.gov/pubmed/35417091
http://dx.doi.org/10.1002/prp2.949
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author Fu, Li
Wasiak, Sylwia
Tsujikawa, Laura M.
Rakai, Brooke D.
Stotz, Stephanie C.
Wong, Norman C. W.
Johansson, Jan O.
Sweeney, Michael
Mohan, Connie M.
Khan, Aneal
Kulikowski, Ewelina
author_facet Fu, Li
Wasiak, Sylwia
Tsujikawa, Laura M.
Rakai, Brooke D.
Stotz, Stephanie C.
Wong, Norman C. W.
Johansson, Jan O.
Sweeney, Michael
Mohan, Connie M.
Khan, Aneal
Kulikowski, Ewelina
author_sort Fu, Li
collection PubMed
description Fabry disease (FD) is a rare X‐linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α‐galactosidase. Gb3 deposits activate immune‐mediated systemic inflammation, ultimately leading to life‐threatening consequences in multiple organs such as the heart and kidneys. Enzyme replacement therapy (ERT), the standard of care, is less effective with advanced tissue injury and inflammation in patients with FD. Here, we showed that MCP‐1 and TNF‐α cytokine levels were almost doubled in plasma from ERT‐treated FD patients. Chemokine receptor CCR2 surface expression was increased by twofold on monocytes from patients with low eGFR. We also observed an increase in IL12B transcripts in unstimulated peripheral blood mononuclear cells (PBMCs) over a 2‐year period of continuous ERT. Apabetalone is a clinical‐stage oral bromodomain and extra terminal protein inhibitor (BETi), which has beneficial effects on cardiovascular and kidney disease related pathways including inflammation. Here, we demonstrate that apabetalone, a BD2‐selective BETi, dose dependently reduced the production of MCP‐1 and IL‐12 in stimulated PBMCs through transcriptional regulation of their encoding genes. Reactive oxygen species production was diminished by up to 80% in stimulated neutrophils following apabetalone treatment, corresponding with inhibition of NOX2 transcription. This study elucidates that inhibition of BET proteins by BD2‐selective apabetalone alleviates inflammatory processes and oxidative stress in innate immune cells in general and in FD. These results suggest potential benefit of BD2‐selective apabetalone in controlling inflammation and oxidative stress in FD, which will be further investigated in clinical trials.
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spelling pubmed-90072222022-04-15 Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy Fu, Li Wasiak, Sylwia Tsujikawa, Laura M. Rakai, Brooke D. Stotz, Stephanie C. Wong, Norman C. W. Johansson, Jan O. Sweeney, Michael Mohan, Connie M. Khan, Aneal Kulikowski, Ewelina Pharmacol Res Perspect Original Articles Fabry disease (FD) is a rare X‐linked disorder of lipid metabolism, characterized by the accumulation of globotriaosylceramide (Gb3) due to defective the lysosomal enzyme, α‐galactosidase. Gb3 deposits activate immune‐mediated systemic inflammation, ultimately leading to life‐threatening consequences in multiple organs such as the heart and kidneys. Enzyme replacement therapy (ERT), the standard of care, is less effective with advanced tissue injury and inflammation in patients with FD. Here, we showed that MCP‐1 and TNF‐α cytokine levels were almost doubled in plasma from ERT‐treated FD patients. Chemokine receptor CCR2 surface expression was increased by twofold on monocytes from patients with low eGFR. We also observed an increase in IL12B transcripts in unstimulated peripheral blood mononuclear cells (PBMCs) over a 2‐year period of continuous ERT. Apabetalone is a clinical‐stage oral bromodomain and extra terminal protein inhibitor (BETi), which has beneficial effects on cardiovascular and kidney disease related pathways including inflammation. Here, we demonstrate that apabetalone, a BD2‐selective BETi, dose dependently reduced the production of MCP‐1 and IL‐12 in stimulated PBMCs through transcriptional regulation of their encoding genes. Reactive oxygen species production was diminished by up to 80% in stimulated neutrophils following apabetalone treatment, corresponding with inhibition of NOX2 transcription. This study elucidates that inhibition of BET proteins by BD2‐selective apabetalone alleviates inflammatory processes and oxidative stress in innate immune cells in general and in FD. These results suggest potential benefit of BD2‐selective apabetalone in controlling inflammation and oxidative stress in FD, which will be further investigated in clinical trials. John Wiley and Sons Inc. 2022-04-13 /pmc/articles/PMC9007222/ /pubmed/35417091 http://dx.doi.org/10.1002/prp2.949 Text en © 2022 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Fu, Li
Wasiak, Sylwia
Tsujikawa, Laura M.
Rakai, Brooke D.
Stotz, Stephanie C.
Wong, Norman C. W.
Johansson, Jan O.
Sweeney, Michael
Mohan, Connie M.
Khan, Aneal
Kulikowski, Ewelina
Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy
title Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy
title_full Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy
title_fullStr Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy
title_full_unstemmed Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy
title_short Inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from Fabry disease patients receiving enzyme replacement therapy
title_sort inhibition of epigenetic reader proteins by apabetalone counters inflammation in activated innate immune cells from fabry disease patients receiving enzyme replacement therapy
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9007222/
https://www.ncbi.nlm.nih.gov/pubmed/35417091
http://dx.doi.org/10.1002/prp2.949
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