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.