DISRUPTED LIPID MEDIATOR NETWORKS LINK SYSTEMIC INFLAMMATION TO BRAIN PATHOLOGY IN X-LINKED ADRENOLEUKODYSTROPHY

X-linked adrenoleukodystrophy (X-ALD) is a devastating neurometabolic disorder caused by loss-of-function mutations in the peroxisomal transporter ABCD1. It manifests as two main phenotypes: lethal childhood cerebral form (cALD), with rapidly progressive neuroinflammation and demyelination, and adult adrenomyeloneuropathy (AMN), characterized by chronic low-grade inflammation and neuropathy. Defective peroxisomal β-oxidation of very long-chain fatty acids leads to profound lipid dysregulation, but how this drives distinct X-ALD inflammatory phenotypes remains unclear.
We investigated lipid-mediated resolution of inflammation across X-ALD phenotypes to gain insights into the interplay between lipid metabolism and neuroinflammation. Specialized pro-resolving mediators (SPMs) and pro-inflammatory lipid mediators (PILMs) were measured in plasma and brain samples using LC-MS/MS. Enzyme activity and expression levels of lipid mediator biosynthetic enzymes (ALOX) were assessed by chiral analysis in plasma and bulk-RNAseq on PBMCs, respectively.
cALD patients exhibited a non-resolving, pro-inflammatory profile, with markedly reduced SPM and highest PILM plasma levels, accompanied by disrupted biosynthetic pathways due to decreased enzyme activity and dysregulated gene expression of ALOX5/15. Brain mirrored cALD plasma findings with significant depletion of SPMs. In contrast, AMN patients displayed a pro-resolutive plasma signature with SPM in control range and modest PILM increase. Five lipid mediators significantly correlated with the disease severity scores on MRI.
These findings uncover deficient ALOX-driven resolution of inflammation as a key driver of severe inflammation in cALD, supporting a mechanistic link between disrupted lipid networks and neuroinflammation. Correlations between lipid mediators and disease severity highlight their potential as biomarkers and therapeutic targets for X-ALD.