biostudies-literatureZierfuss BAustrian Science Fund FWF305https://www.ebi.ac.uk/biostudies/studies/S-EPMC9759912biostudies-literatureUnknown19(1)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 prJournal of neuroinflammationSaturated very long-chain fatty acids regulate macrophage plasticity and invasiveness.PMC9759912KLI 837DOC 33-B27DOC 33KLI 837-BVandersteene SWaidhofer-Sollner PWeinhofer IGrabmeier-Pfistershammer KBerger JVilloria-Gonzalez AKemp SBuda AForss-Petter SFabjan JBattin CZierfuss BSteinberger PLogist MDijkstra IMEParzer PfalseSaturated very long-chain fatty acids regulate macrophage plasticity and invasiveness.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 pr2022-01-01T00:00:00Z2022 Dec2026-05-28T21:28:25.839Z2025-02-19T03:24:45.745ZS-EPMC97599123652861610.1186/s12974-022-02664-y