The role of astrocyte phenotypes in acute MS lesions

Astrocytes have been associated with both neurodegeneration and recovery of neuronal damage in MS [1–4]. While transforming growth factor alpha (TGF-α) induces an anti-inflammatory astrocyte phenotype, vascular endothelial growth factor B (VEGF-B) induces a pro-inflammatory astrocyte polarization. Results now show that TGF-α/VEGF-B ratios can serve as a novel prognostic biomarker for acute and chronic MS lesions [5].

Dr Veit Rothhammer (University of Erlangen-Nürnberg, Germany) discussed the role of astrocyte phenotypes in acute autoimmune inflammatory CNS lesions.

A key protein in the anti-inflammatory astrocyte phenotype is the aryl hydrocarbon receptor (AHR), which mediates protective effects of neural tissue and can be activated by binding of its ligands, originating from the gut microbiome or dietary factors. The activation of AHR is associated with an inhibition of immune cell recruitment, reduced neuron and oligodendrocyte death, and a decreased activation of monocytes [1]. A comparison of AHR ligand serum levels between patients with relapsing-remitting MS and healthy controls demonstrated a decreased level of AHR ligands in patients with MS. This result suggests that glial regeneration mechanisms are reduced in these patients, whereas inflammation, neurodegeneration, and immune cell recruitment are increased [6,7].

In vitro analysis of microglial AHR deletion showed that TGF-α and VEGF-B are potential up-stream regulators for astrocytes. TGF-α was associated with an anti-inflammatory phenotype of astrocytes, whereas VEGF-B induced a pro-inflammatory phenotype of astrocytes. In vivo analysis confirmed the role of microglia-derived TGF-α and VEGF-B in astrocyte phenotype expression [2,3].

Next, Dr Rothhammer addressed the question of whether the TGF-α/VEGF-B ratio and AHR ligand levels could serve as biomarkers in MS. A recent study showed that a decreasing TGF-α/VEGF-B ratio is significantly associated with increased disease severity in MS (P=0.0161). Similarly, reduced rates of AHR agonistic activity were associated with more severe disease (P=0.0158). Finally, AHR ligand levels predicted the time of conversion from clinically isolated syndrome to definite MS. Higher AHR agonistic activity was associated with a longer time to definite MS diagnosis (P=0.0102) [8].

In conclusion, AHR ligands are decreased in MS patients, which leads to a more pro-inflammatory phenotype of astrocytes. AHR depletion in microglia is associated with reduced TGF-α levels, and increased VEGF-B levels, indirectly stimulating a pro-inflammatory phenotype of astrocytes. TGF-α/VEGF-B ratios and AHR ligand levels have potential in measuring disease activity and predicting a patient’s progression to a more severe type of MS.

1. Rothhammer V, et al. Nature Medicine. 2016;22:586–597.
2. Liddelow SA, et al. Nature. 2017;541:481–487.
3. Rothhammer V, et al. Nature. 2018;557:724–728.
4. Wheeler MA, et al. Cell. 2019;176(3):581-596.
5. Rothhammer V, et al. Astrocyte phenotypes and interactions in acute autoimmune inflammatory CNS lesions. OP058, ECTRIMS 2021 Virtual Congress, 13–15 October.
6. Rothhammer V, et al. Sci Rep. 2018;8(1):4970.
7. Rothhammer V, et al. Neurol Neuroimmunol Neuoinflamm. 2017;4(4):e359.
8. Cirac A, et al. Neurol Neuroimmunol Neuroinflamm. 2021;8(5):e1043.

 

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Posted on 9 December, 202118 March, 2024