Active liver X receptor signaling in phagocytes in multiple sclerosis lesions
Jo Mailleux1, Tim Vanmierlo1, Jeroen Fj Bogie1
1Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium.
Objective:
We sought to determine the liver X receptor (LXR) ligands present in human macrophages after myelin phagocytosis and whether LXRs are activated in multiple sclerosis (MS) lesions.
Methods:
We used real-time quantitative polymerase chain reaction (PCR) and immunohistochemistry to determine expression of LXRs and their response genes in human phagocytes after myelin phagocytosis and in active MS lesions. We used gas chromatographic/mass spectrometric analysis to determine LXR-activating oxysterols and cholesterol precursors present and formed in myelin and myelin-incubated cells, respectively.
Results:
Myelin induced LXR response genes ABCA1 and ABCG1 in human monocyte-derived macrophages. In active MS lesions, we found that both gene expression and protein levels of ABCA1 and apolipoprotein E ( APOE) are upregulated in foamy phagocytes. Moreover, we found that the LXR ligand 27-hydroxycholesterol (27OHC) is significantly increased in human monocyte-derived macrophages after myelin uptake.
Conclusion:
LXR response genes are upregulated in phagocytes present in active MS lesions, indicating that LXRs are activated in actively demyelinating phagocytes. In addition, we have shown that myelin contains LXR ligands and that 27OHC is generated in human monocyte-derived macrophages after myelin processing. This suggests that LXRs in phagocytes in active MS lesions are activated at least partially by (oxy)sterols present in myelin and the generation thereof during myelin processing.
Insights
Liver X receptors (LXRs) are activated in multiple sclerosis (MS) lesions. Myelin processing in macrophages increases LXR ligands like 27-hydroxycholesterol, suggesting a role in demyelination.
Area of Science:
- Neuroimmunology
- Cellular Biology
- Molecular Medicine
Background:
- Multiple sclerosis (MS) is a demyelinating disease of the central nervous system.
- Phagocytes play a critical role in myelin debris clearance during demyelination.
- Liver X receptors (LXRs) are nuclear receptors involved in cholesterol homeostasis and inflammation.
Purpose of the Study:
- To identify liver X receptor (LXR) ligands in human macrophages after myelin phagocytosis.
- To investigate LXR activation in active multiple sclerosis (MS) lesions.
- To determine the role of myelin-derived lipids in LXR activation during demyelination.
Main Methods:
- Real-time quantitative PCR and immunohistochemistry to assess LXR and response gene expression.
- Gas chromatography/mass spectrometry to identify oxysterols and cholesterol precursors.
- Myelin incubation assays with human monocyte-derived macrophages.
Main Results:
- Myelin induced LXR response genes (ABCA1, ABCG1) in macrophages.
- ABCA1 and apolipoprotein E (APOE) were upregulated in foamy phagocytes in active MS lesions.
- 27-hydroxycholesterol (27OHC), an LXR ligand, increased in macrophages after myelin uptake.
Conclusions:
- LXR response genes are upregulated in phagocytes within active MS lesions.
- LXRs are activated in actively demyelinating phagocytes in MS.
- Myelin contains LXR ligands, and 27OHC is generated during myelin processing, suggesting LXR activation by myelin-derived lipids in MS lesions.
