image: DHA-TAGs are associated with microglia activation and transmigration of lymphocytes into the brain following ictus. Sequestration of PUFAs within PEs promotes astrogliogenesis and suppresses ferroptotic deaths of astrocytes to enhance neuronal survival. Increases in VLC-Cer over SM promote exosome secretion that ameliorates neuroinflammation. SPP1 secreted by microglia and astrocytes promotes remyelination of oligodendrocytes following ictus, positively reinforced by LPA signaling and the accretions in glycosphingolipid precursors (GalCer and SL) stemming from abated degradation attributed to diminished levels of lysosomal degradative enzymes (Galc, Asah 1 and HexA & B).
Credit: ©Science China Press
This study is led by Professor Rong Hu’s team from the Department of Neurosurgery and Key Laboratory of Neurotrama, Southwest Hospital, Third Military Medical University (Army Medical University, Chongqing), in collaboration with the research team led by Professor Guanghou Shui from the State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences (Beijing). This study performed in-depth multi-omics analyses, comprising a total of 772 metabolites (including lipids, polar metabolites, oxysterols and sterols) and 2325 proteins on CSF samples from 50 ICH patients (collected at four time-points from Day 1 to Day 14) and 22 control participants. It revealed that lipids were the most significantly altered metabolites at ICH onset, accounting for more 70%, demonstrating the clinical relevance of lipids in ICH pathology.
Stark elevations in polyunsaturated docosahexaenoic acids (DHA) containing TAGs and concomitant reductions in saturated fatty acyl-containing TAGs were observed. Increases in polyunsaturated arachidonic acids containing phosphatidylethanolamines (PEs) were noted. Very long-chain sphingomyelins (SMs) were elevated at ICH onset and progressively decreased during the onset-to-reperfusion phase which consequentially resulted in progressive increases in very long-chain ceramide (Cer) and very long-chain galactosylceramide (GalCer). This demonstrated the enhanced conversions of very long-chain SMs to its corresponding Cers and complex glycosylated sphingolipids during the onset-to-reperfusion (Day 1 to Day 14) phase. Specific TAGs might be functionally associated with pro-resolving monocytes and macrophages. TAGs containing saturated fatty acyls were gradually increased during the onset-to-reperfusion phase. Furthermore, this study discovered that restoration of TAG profiles during onset-to-reperfusion phase was significantly associated with better prognosis over the next 12 months post-ICH in the mild (mRS=3) and moderate (mRS=4) groups.
Interrogation of changes in CSF proteomics relative to controls to consolidate functional implications of the observed lipid alterations, revealed stark rise in proteasome complex protein components with concomitant decreases in SPP1, a potent stimulator of remyelination following demyelination. Sphingolipid degradation pathway was downregulated, specifically galactocerebrosidase (Galc), acid ceramidase (Asah1) and beta-hexosaminidase subunits alpha and beta (HexA, HexB) which degrade GalCer, Cer and GM2 gangliosides respectively, were markedly reduced post-ICH. Together in combination with lipidomic findings, it emphasized that increases in very-long-chain (C22-C26) GalCer and sulfatides (SL) were attributed to attenuated degradation, which may serve to foster active remyelination and re-established neuronal connections following ictus.
Our multi-omics CSF datasets presented in this study represented a valuable resource toward comprehending the key metabolic events in the brain micromilieu following ictus. Trans-omics integration of data revealed that circulating TAGs are implicated in the modulation of immune cell activity and inflammation, while changes in glycosphingolipid potentially reflected demyelination and remyelination mediated by proteasomal degradation of SPP1 in the CSF. Our findings underscore lipid-centric intervention targets to ameliorate metabolic insults post-ICH.
See the article:
CSF multi-omics of intracerebral hemorrhage from onset to reperfusion underscores lipid metabolism in functional outcome
Journal
Science Bulletin