Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination

Activation of innate immunity within demyelinated regions during cuprizone treatment lasts about 1 month, which is shorter than the 2-4 months necessary for progression onset in NOD animals.

“It is worth noting, indeed, that activation of innate immunity within demyelinated regions during cuprizone treatment (Fig. 2 and (Skripuletz et al. 2013)) lasts for an extent of time of about 1 month that is shorter than that of 2–4 months necessary for progression onset in NOD animals (Buonvicino et al. 2019).”

CXCL10 is an important attractant for microglia during cuprizone treatment.

“– an important attractant for microglia during cuprizone treatment [184–186].”

Astrocytes secrete CXCL10 in vitro following stimulation with IFN-γ or TNF-α.

“Astrocytes were also shown to secrete CXCL10 in vitro following stimulation with IFN-γ or TNF-α [185].”

Astrocytes are responsible for the recruitment of microglia.

“It was concluded, that astrocytes are responsible for the recruitment of microglia.”

Ablation of astrocytes during cuprizone-induced demyelination resulted in diminished activation and invasion of microglia into the demyelinated lesion.

“but resulted in a diminished activation and invasion of microglia into the demyelinated lesion.”

As a consequence of astrocyte ablation, removal of myelin debris was delayed and subsequent OPC proliferation and remyelination were delayed.

“As a consequence the removal of myelin debris was delayed and subsequent OPC proliferation and remyelination were delayed.”

Ablation of astrocytes during cuprizone-induced demyelination had no impact on the loss of mature oligodendrocytes and on axonal damage.

“Ablation of astrocytes during cuprizone-induced demyelination had no impact on the loss of mature oligodendrocytes and on axonal damage, but resulted in a diminished activation and invasion of microglia into the demyelinated lesion.”

Depletion of astrocytes resulted in diminished numbers of mature oligodendrocytes during remyelination.

“In addition, the depletion of astrocytes resulted in diminished numbers of mature oligodendrocytes during remyelination (Skripuletz et al., 2013).”

Astrocyte-derived factors mediate attraction of microglia.

“arguing for astrocyte-derived factors that mediate attraction of microglia.”

In astrocyte-ablated mice, clearance of damaged myelin and recruitment of microglia were strongly impaired.

“However, the clearance of damaged myelin as well as the recruitment of microglia was strongly impaired in this experimental setting”

Partial ablation of astrocytes in mice challenged for 3 weeks with cuprizone did not reveal any difference in CCL2 and CCL3 expression.

“Interestingly, a partial ablation of astrocytes in mice challenged for 3 weeks with cuprizone did not reveal any difference in CCL2 and CCL3 expression”

We detected up-regulated expression of CCL2 and CCL3 upon cuprizone treatment.

“In line with other studies (McMahon et al., 2001; Buschmann et al., 2012) we could also detect an up-regulated expression of CCL2 and CCL3 upon cuprizone treatment (Skripuletz et al., 2013).”

Treatment of astrocyte cultures with LPS, IL-1β, or TNF-α led to an enhancement of CXCL10 production in vitro.

“and the treatment of astrocyte cultures with LPS, IL-1β, or TNF-α led to an enhancement of CXCL10 production in vitro (Skripuletz et al., 2013).”

CXCL10 mRNA expression was reduced in astrocyte-depleted mice.

“Our studies suggested that this process may be regulated by the chemokine CXCL10 since CXCL10 mRNA expression was reduced in the astrocyte-depleted mice”

This process may be regulated by the chemokine CXCL10.

“Our studies suggested that this process may be regulated by the chemokine CXCL10”

CCL2 and CCL3 are not astrocyte-derived at least at this time point.

“suggesting that these cytokines are not astrocyte-derived at least at this time point (Skripuletz et al., 2013).”