TY - JOUR
T1 - Saturated very long-chain fatty acids regulate macrophage plasticity and invasiveness
AU - Zierfuss, Bettina
AU - Buda, Agnieszka
AU - Villoria-González, Andrea
AU - Logist, Maxime
AU - Fabjan, Jure
AU - Parzer, Patricia
AU - Battin, Claire
AU - Vandersteene, Streggi
AU - Dijkstra, Inge M. E.
AU - Waidhofer-Söllner, Petra
AU - Grabmeier-Pfistershammer, Katharina
AU - Steinberger, Peter
AU - Kemp, Stephan
AU - Forss-Petter, Sonja
AU - Berger, Johannes
AU - Weinhofer, Isabelle
N1 - Funding Information: We would like to thank all the patients and healthy volunteers who participated in this study. In addition, we are grateful for excellent technical assistance by Martina Rothe. We also acknowledge the help of Prof. Andreas Spittler from the Flow Cytometry Core Facility and of Dr. Michael Schuster from the Biomedical Sequencing Facility of the Medical University of Vienna, Austria. Funding Information: This work was supported by the Austrian Science Fund KLI 837-B to IW; DOC 33-B27 to JB, and CCHD/DK W1205 to JB. BZ was supported by a postdoctoral fellowship from Biogen and a joint Fonds de recherche Québec – Santé (FRQS)-MSSC fellowship. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
KW - Extracellular matrix degradation
KW - Immune response
KW - Lipid metabolism
KW - Neuroinflammation
KW - X-linked adrenoleukodystrophy
UR - http://www.scopus.com/inward/record.url?scp=85144224934&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s12974-022-02664-y
DO - https://doi.org/10.1186/s12974-022-02664-y
M3 - Article
C2 - 36528616
SN - 1742-2094
VL - 19
JO - Journal of neuroinflammation
JF - Journal of neuroinflammation
IS - 1
M1 - 305
ER -