Extended Data Fig. 10: Working model.
From: Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis
a, Abca1 expression following squalene (100 µM, left) and DMHCA (10 µM, right) treatment in LPS activated BMDMs (n = 3 cultures) (Student’s t-test, two-sided). b, Expression of inflammatory genes (Tnf, Nos2) in LPS (10 ng/ml) activated WT BMDMs (n = 3 cultures) 24 h after DMHCA (10 µM) treatment. Data normalized to untreated control (n = 3 cultures, set to 1) (two-way ANOVA with Holm-Sidak post test). c, Quantitative RT-PCR analysis determining the expression housekeeping reference genes in spinal cord from EAE mice treated with DMHCA (n = 6 animals) and squalene (n = 6 animals). d, Fold expression profiles of inflammatory genes in CD11b + cells isolated from spinal cord of EAE animals treated with DMHCA (n = 6 animals) and squalene (n = 6 animals) (normalized to vehicle-treated EAE mice, n = 6 animals). Asterisks indicate significant differences between DMHCA and DMHCA/squalene co-treatment (Student’s t-test, two-sided). e, Resulting working model of the relationship between sterol metabolism in microglia/macrophages in an inflammatory demyelinating lesion and myelin repair. (1) Phagocytosis of lipid-rich myelin increases the cellular cholesterol content in microglia/macrophages, which (2) inhibits sterol synthesis by negative feedback regulation. (3) In demyelinating lesions, pro-inflammatory mediators counteract this inhibition and induce sterol synthesis. NRF1/NFE2L1 likely senses intracellular cholesterol excess and represses Dhcr24, leading to the synthesis of the sterol intermediate desmosterol. (4) Increasing desmosterol levels activate LXR-signaling. (5) This leads to LXR-mediated export of cholesterol via ABC transporters (cholesterol recycling) and (6) dampening of the pro-inflammatory phenotype of microglia/macrophages. (7) Resolved inflammation and increased disposition of cholesterol facilitates remyelination by oligodendrocytes. f, In case of normal repair of demyelinated lesions, microglia/macrophages are capable of lipid/cholesterol recycling and switching to an anti-inflammatory signature that depends on desmosterol synthesis. We speculate that this conserved mechanism mediates ‘silent’ regeneration in asymptomatic individuals and in the preclinical phase of MS. When endogenous sterol synthesis is impaired as in our SQS conditional mutants or presumably also during aging or advanced disease, these repair strategies fail leading to cholesterol overloading of microglia/macrophages, persistent inflammation and impaired regeneration. Dietary squalene supplementation supports sterol synthesis. This increases desmosterol levels in microglia/macrophages that facilitates to resolve the local inflammation and to recycle lipid/cholesterol. In addition, squalene promotes cholesterol synthesis by oligodendrocytes for remyelination that collectively enhances repair. Asterisks mark significant changes, ***p < 0.001, **p < 0.01, *p < 0.05.
