Format

Send to

Choose Destination

See 1 citation:

Brain. 2018 May 30. doi: 10.1093/brain/awy127. [Epub ahead of print]

Impaired plasticity of macrophages in X-linked adrenoleukodystrophy.

Author information

1
Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
2
Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
3
Institute of Neuropathology, University Medical Center Goettingen, Germany.
4
Department of Clinical Science, Intervention and Technology; Karolinska Institutet, Stockholm, Sweden.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, UK.
6
Children's Cancer Research Institute, Vienna, Austria.
7
Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
8
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
9
Institute of Immunology, Medical University of Vienna, Vienna, Austria.
10
Department of Neurology, University Hospital Leipzig, Leipzig, Germany.
11
Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Abstract

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.

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center