Microglial control of astrocytes in an experimental model of multiple sclerosis.

Multiple sclerosis is a chronic inflammatory degenerative disease of the central nervous system (CNS) mainly characterized by activation of cells such as microglia and astrocytes, death of oligodendrocytes (cells wrapping around neuronal processes –the axons– constituting a so-called myelin sheath that enables a correct neuronal functioning) and axonal degeneration, all resulting into severe neurologic dysfunctions.

Microglia and astrocytes have been recently shown to play a key role in disease progression; specifically, through the reduced VEGFb expression and increased TGFa expression induced by the microglial AHR receptor.

How does the increased TGFa and decreased VEGFb expression affect neurodegeneration? The effect is exerted through the action of these two molecules on astrocytes.

TGFa and VEGFb bind to specific receptors on astrocytes (named ErbB1 and FLT1 respectively). Upon binding, opposite effects are exerted: on one side, TGFa/ErbB1 reduces the release of neurotoxic factors by astrocytes, hence resulting into a neuroprotective effect. On the other side, VEGFb/FLT1 interaction upregulates neurotoxic and neuroinflammatory factors, thus worsening neurodegeneration.

This mechanism has been recently described in an experimental mouse model of multiple sclerosis.

Moreover, AHR, TGFa and VEGFb expression have been detected also in human brain samples from multiple sclerosis patients, corroborating the results obtained with experimental models.

Furthermore, AHR activity, and its downstream effect, is also modulated by the binding of a molecule, I3S, deriving from the metabolism of tryptophan, an amino acid commonly assumed through the diet and metabolized by gut bacteria. I3S binding to AHR results into reduced VEGFb expression and thus decreased astrocyte pathogenic activity (reduced CNS inflammation) and limited multiple sclerosis-like development in experimental models.

These recent findings have multiple implications. Defining the mechanism underlying the modulatory, potentiating effect of VEGFb on astrocytes-mediated CNS inflammation would pave the way to the identification of specific inhibitors of this mechanism as potential therapeutics against CNS inflammation and associated diseases. Finally, the identified link between astrocytes pathogenicity and tryptophan metabolism might provide another (easier?) tool to interfere with CNS inflammation by modulating dietary tryptophan metabolism.

Reference: Microglial control of astrocytes in response to microbial metabolites. Rothhammer V, Borucki DM, Tjon EC, Takenaka MC, Chao CC, Ardura-Fabregat A, de Lima KA, Gutiérrez-Vázquez C, Hewson P, Staszewski O, Blain M, Healy L, Neziraj T, Borio M, Wheeler M, Dragin LL, Laplaud DA, Antel J, Alvarez JI, Prinz M, Quintana FJ. Nature. 2018