Transcriptome of human primary macrophages from X-linked adrenoleukodystrophy patients and healthy controls before and after long-term myelin phagocytosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE245235 | GEO | 2023/10/12
REPOSITORIES: GEO
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Project description:CD14+ monocytes were isolated from the blood of healthy human donors by Ficoll density-gradient centrifugation, magnetic cell sorting and LS column systems. CD14+ monocytes were in vitro differentiated to macrophages by culturing the cells for 7 days in RPMI medium containing 10% FCS, 1% penicillin/streptomycin, 1% glutamine, 1% Fungizone and supplemented with 50 ng/ml human macrophage-colony stimulating factor (M-CSF) in the presence or absence of myelin isolated from brain tissue of 6-8 week-old wild-type C57BL6/J mice.
2023-11-22 | GSE245015 | GEO
Project description:Transcriptome of human primary macrophages from X-linked adrenoleukodystrophy patients and healthy controls before and after long-term myelin phagocytosis
| PRJNA1027446 | ENA
Project description:Transcriptome of human primary macrophages from healthy controls after long-term myelin phagocytosis
| PRJNA1026622 | ENA
Project description:Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD). The severest form, inherited dysfunction of the VLCFA transporter ABCD1, underlying X-ALD, causes brain myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Using whole transcriptome sequencing of X-ALD macrophages, we revealed that VLCFAs prime human macrophage membranes for inflammation and increase factors involved in chemotaxis and invasion. When applied externally, mimicking lipid destruction in X-ALD lesions, VLCFAs did not activate toll-like receptors in healthy cells but 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 accumulated in healthy macrophages but were rapidly cleared with onset of resolution by increasing VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity.
2022-11-09 | GSE217140 | GEO
Project description:Traumatic injuries of the central nervous system (CNS) are followed by the accumulation of cellular debris including proteins and lipids from myelinated fiber tracts. Insufficient phagocytic clearance of myelin debris influences the pathological process because it induces inflammation and blocks axonal regeneration. We investigated whether ligands of nuclear receptor families retinoic acid receptors (RARs), retinoid X receptors, peroxisome proliferator-activated receptors, lipid X receptors, and farnesoid X receptors increase myelin phagocytosis by murine bone marrow-derived macrophages and Raw264.7 cells. Using in vitro assays with 3,3'-dioctadecyloxacarbocyanine perchlorate- and pHrodo-labeled myelin we found that the transcriptional activator all-trans retinoic acid (RA)enhanced endocytosis of myelin involving the induction of tissue transglutaminase-2. The RAR-dependent increase of phagocytosis was not associated with changes in gene expression of receptors FcγR1, FcγR2b, FcγR3, TREM2, DAP12, CR3, or MerTK. The combination of RA and myelin exposure significantly reduced the expression of M1 marker genes inducible nitric oxide synthase and interleukin-1β and increased expression of transmembrane proteins CD36 and ABC-A1, which are involved in lipid transport and metabolism. The present results suggest an additional mechanism for therapeutic applications of RA after CNS trauma. It remains to be studied whether endogenous RA-signaling regulates phagocytosis in vivo.
| S-EPMC7984038 | biostudies-literature
Project description:X-linked adrenoleukodystrophy is caused by ATP-binding cassette transporter D1 (ABCD1) mutations and manifests by default as slowly progressive spinal cord axonopathy with associated demyelination (adrenomyloneuropathy). In 60% of male cases, however, X-linked adrenoleukodystrophy converts to devastating cerebral inflammation and demyelination (cerebral adrenoleukodystrophy) with infiltrating blood-derived monocytes and macrophages and cytotoxic T cells that can only be stopped by allogeneic haematopoietic stem cell transplantation or gene therapy at an early stage of the disease. Recently, we identified monocytes/macrophages but not T cells to be severely affected metabolically by ABCD1 deficiency. Here we found by whole transcriptome analysis that, although monocytes of patients with X-linked adrenoleukodystrophy have normal capacity for macrophage differentiation and phagocytosis, they are pro-inflammatory skewed also in patients with adrenomyloneuropathy in the absence of cerebral inflammation. Following lipopolysaccharide activation, the ingestion of myelin debris, normally triggering anti-inflammatory polarization, did not fully reverse the pro-inflammatory status of X-linked adrenoleukodystrophy macrophages. Immunohistochemistry on post-mortem cerebral adrenoleukodystrophy lesions reflected the activation pattern by prominent presence of enlarged lipid-laden macrophages strongly positive for the pro-inflammatory marker co-stimulatory molecule CD86. Comparative analyses of lesions with matching macrophage density in cases of cerebral adrenoleukodystrophy and acute multiple sclerosis showed a similar extent of pro-inflammatory activation but a striking reduction of anti-inflammatory mannose receptor (CD206) and haemoglobin-haptoglobin receptor (CD163) expression on cerebral adrenoleukodystrophy macrophages. Accordingly, ABCD1-deficiency leads to an impaired plasticity of macrophages that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy that only in rare cases arrests spontaneously. These findings emphasize monocytes/macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.
| S-EPMC6061697 | biostudies-literature
Project description:X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above-mentioned diseases. Applying recently established microglia markers to human autopsy cases of X-ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune-phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full-blown myelin degeneration both in X-ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X-ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.
| S-EPMC6594046 | biostudies-literature
Project description:Transcriptome of human primary macrophages from X-linked adrenoleukodystrophy patients and healthy controls
| PRJNA896999 | ENA
Project description:Study objectivesAssess the short- and long-term stability of sleep duration in patients with insomnia and normal-sleeping controls.DesignObservational short-term and prospective studies.SettingSleep laboratory.ParticipantsPatients with insomnia (n = 150) and controls (n = 151) were recruited from the local community or sleep disorders clinic. A subsample of 95 men from the Penn State Adult Cohort (PSAC) were followed up 2.6 y after their initial visit.MeasurementsParticipants underwent a physical examination and 8-h polysomnography (PSG) recording for 3 consecutive nights (controls and insomniacs), or 2 single nights separated by several years (PSAC). Intraclass correlation coefficients (ICCs) assessed the stability of the variables total sleep time (TST), sleep onset latency (SOL), and wake after sleep onset (WASO). We also examined persistence of the first-night classification of "short" versus "normal" sleep duration on subsequent nights.ResultsStability of TST, SOL, and WASO based on 1 night were slight to moderate in both patients with insomnia (ICC = 0.37-0.57) and controls (ICC = 0.39-0.59), and became substantial to almost perfect when based on the average of 3 nights (ICC = 0.64-0.81). We observed similar degrees of stability for TST and WASO in the longitudinal sample, with moderate stability based on a single night and substantial stability based on both nights. In examining the persistence of "short" and "normal" sleep duration, 71.4% (controls), 74.7% (patients with insomnia), and 72.6% (longitudinal sample) of participants retained their first-night classifications over subsequent nights.ConclusionsSleep duration variables, particularly total sleep time based on 3 consecutive nights in both patients with insomnia and controls or two single-night recordings separated by several years, are stable and reflect a person's habitual sleep. Furthermore, a single night in the laboratory may be useful for reliably classifying one's sleep duration.
| S-EPMC4813370 | biostudies-literature
Project description:ImportanceAllogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized.ObjectivesTo identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes.Design, setting, and participantsThis case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score.Main outcomes and measuresOverall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients' clinical symptoms, demyelination patterns, and stem cell source were stratified.ResultsOf the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6).Conclusions and relevanceAll patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.
| S-EPMC6324299 | biostudies-literature