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By Jamshed Arslan Pharm.D., PhD.
Myelin is a cholesterol-rich layer around nerves. Damage to this protective layer and the consequent slowing down of nerve impulses are hallmarks of multiple sclerosis (MS) and other demyelinating diseases. Myelin breakdown alters plasma levels of 27-hydroxycholesterol (27OHC) and other CNS-specific oxysterols, which are natural ligands of transcription factors called liver X receptors (LXRs). Since myelin phagocytosis is a source of intracellular oxysterols in the resident microglia and infiltrating macrophages, a team of scientists in Europe decided to test the hypothesis that myelin uptake and subsequent formation of oxysterols activates LXRs in phagocytes in MS. They found that myelin uptake by human monocyte-derived macrophages (MDMs) induced LXR response genes (ABCA1, ABCG1) and increased 27OHC levels. As expected, the resident microglia and infiltrated macrophages had enhanced LXR alpha and elevated gene and protein levels of LXR downstream targets (ABCA1, APOE) in MS lesions.
Immunocytochemistry/Immunofluorescence: Apolipoprotein E/ApoE Antibody [NBP2-41216] - Staining of APO E in mouse brain tissue with APO E Antibody at 20 ug/mL.
To study the effect of myelin uptake on MDMs, the researchers studied the expression of LXR alpha, LXR beta, and LXR downstream targets APOE, ABCA1 and ABCG1 in myelin-treated MDMs through real-time PCR. Heightened mRNA expression of LXR alpha, ABCA1 and ABCG1 suggested that LXR alpha is the prominent driver behind myelin-induced LXR signaling in MDMs. The mRNA expression of LXR alpha and its downstream targets ABCA1 and APOE were also high in the active MS lesions, compared to control brain tissue samples. Immunohistochemical analysis on demyelinating MS lesions revealed that HLA-DR phagocytes with foamy appearance had high expression of ABCA1, APOE, and LXR alpha/beta. These results indicate LXR activation in phagocytes in MS lesions.
The next step was to see if myelin uptake by MDMs could increase the intracellular oxysterols, which could in turn induce LXR target gene expression.
To investigate how myelin uptake might increase LXR response gene expression, the team analyzed the levels of cholesterol, desmosterol (an LXR ligand), and oxysterols (27OHC, 24OHC) in human macrophages incubated with myelin for 5 days. The GC/MS analysis showed increased levels of 27OHC, but not 24OHC, cholesterol or desmosterol, in myelin-treated cells relative to untreated controls. In this experiment, the concentration of 27OHC was about 5μM per 1 million macrophages. Treating MDMs with 5μM 27OHC enhanced gene expression of LXR alpha, ABCA1 and ABCG1, indicating that the level of 27OHC induction by myelin uptake is enough to activate LXRs.
Simply put, the researchers were able to show LXR activation in myelin-ingesting macrophages in the active MS lesions, using PCR, immunohistochemistry and GC/MS analysis.
The study identifies targeting LXR signaling as a potential approach in treating demyelinating neurodegenerative disorders. This research has implications for inflammatory brain diseases since ligand-activated LXRs exhibit anti-inflammatory properties in CNS and immune cells.
Jamshed Arslan, Pharm D., PhD.
University of Alabama at Birmingham, School of Medicine
Dr. Arslan studies cell signaling in mitochondrial defects in
C. elegans and transgenic mice.
References
Mailleux, Jo, et al. "Active Liver X Receptor Signaling in Phagocytes in Multiple Sclerosis Lesions." Multiple Sclerosis Journal, vol. 24, no. 3, 2018, pp. 279–289. DOI: 10.1177/1352458517696595
