Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness
Abstract Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD) due to inherited dysfunction of the peroxisomal VLCFA transporter ABCD1. In its severest form, X-ALD causes cerebral myelin destruction...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02664-y |
| _version_ | 1797980487481819136 |
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| author | Bettina Zierfuss Agnieszka Buda Andrea Villoria-González Maxime Logist Jure Fabjan Patricia Parzer Claire Battin Streggi Vandersteene Inge M. E. Dijkstra Petra Waidhofer-Söllner Katharina Grabmeier-Pfistershammer Peter Steinberger Stephan Kemp Sonja Forss-Petter Johannes Berger Isabelle Weinhofer |
| author_facet | Bettina Zierfuss Agnieszka Buda Andrea Villoria-González Maxime Logist Jure Fabjan Patricia Parzer Claire Battin Streggi Vandersteene Inge M. E. Dijkstra Petra Waidhofer-Söllner Katharina Grabmeier-Pfistershammer Peter Steinberger Stephan Kemp Sonja Forss-Petter Johannes Berger Isabelle Weinhofer |
| author_sort | Bettina Zierfuss |
| collection | DOAJ |
| description | Abstract Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD) due to inherited dysfunction of the peroxisomal VLCFA transporter ABCD1. In its severest form, X-ALD causes cerebral myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Here, whole transcriptome sequencing of X-ALD macrophages indicated that VLCFAs prime human macrophage membranes for inflammation and increased expression of factors involved in chemotaxis and invasion. When added externally to mimic lipid release in demyelinating X-ALD lesions, VLCFAs did not activate toll-like receptors in primary macrophages. In contrast, VLCFAs provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix-degrading enzymes and chemokine release. Following pro-inflammatory LPS activation, VLCFA levels increased also in healthy macrophages. With the onset of the resolution, VLCFAs were rapidly cleared in control macrophages by increased peroxisomal VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression upon LPS treatment. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity. |
| first_indexed | 2024-04-11T05:55:07Z |
| format | Article |
| id | doaj.art-28432a9f70e04eb791392053b1e9a1b7 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T05:55:07Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-28432a9f70e04eb791392053b1e9a1b72022-12-22T04:41:55ZengBMCJournal of Neuroinflammation1742-20942022-12-0119112010.1186/s12974-022-02664-ySaturated very long-chain fatty acids regulate macrophage plasticity and invasivenessBettina Zierfuss0Agnieszka Buda1Andrea Villoria-González2Maxime Logist3Jure Fabjan4Patricia Parzer5Claire Battin6Streggi Vandersteene7Inge M. E. Dijkstra8Petra Waidhofer-Söllner9Katharina Grabmeier-Pfistershammer10Peter Steinberger11Stephan Kemp12Sonja Forss-Petter13Johannes Berger14Isabelle Weinhofer15Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDivision of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaGenetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, University of AmsterdamDivision of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of ViennaDivision of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of ViennaDivision of Immune Receptors and T Cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of ViennaGenetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Center, Amsterdam Neuroscience, Amsterdam Gastroenterology Endocrinology Metabolism, University of AmsterdamDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaDepartment of Pathobiology of the Nervous System, Center for Brain Research, Medical University of ViennaAbstract Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD) due to inherited dysfunction of the peroxisomal VLCFA transporter ABCD1. In its severest form, X-ALD causes cerebral myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Here, whole transcriptome sequencing of X-ALD macrophages indicated that VLCFAs prime human macrophage membranes for inflammation and increased expression of factors involved in chemotaxis and invasion. When added externally to mimic lipid release in demyelinating X-ALD lesions, VLCFAs did not activate toll-like receptors in primary macrophages. In contrast, VLCFAs provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix-degrading enzymes and chemokine release. Following pro-inflammatory LPS activation, VLCFA levels increased also in healthy macrophages. With the onset of the resolution, VLCFAs were rapidly cleared in control macrophages by increased peroxisomal VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression upon LPS treatment. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity.https://doi.org/10.1186/s12974-022-02664-yExtracellular matrix degradationImmune responseLipid metabolismNeuroinflammationX-linked adrenoleukodystrophy |
| spellingShingle | Bettina Zierfuss Agnieszka Buda Andrea Villoria-González Maxime Logist Jure Fabjan Patricia Parzer Claire Battin Streggi Vandersteene Inge M. E. Dijkstra Petra Waidhofer-Söllner Katharina Grabmeier-Pfistershammer Peter Steinberger Stephan Kemp Sonja Forss-Petter Johannes Berger Isabelle Weinhofer Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness Journal of Neuroinflammation Extracellular matrix degradation Immune response Lipid metabolism Neuroinflammation X-linked adrenoleukodystrophy |
| title | Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness |
| title_full | Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness |
| title_fullStr | Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness |
| title_full_unstemmed | Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness |
| title_short | Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness |
| title_sort | saturated very long chain fatty acids regulate macrophage plasticity and invasiveness |
| topic | Extracellular matrix degradation Immune response Lipid metabolism Neuroinflammation X-linked adrenoleukodystrophy |
| url | https://doi.org/10.1186/s12974-022-02664-y |
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