Astrocyte to microglia cross-talk in acute and chronic neuroinflammation is shaped by SFRP1

Neuroinflammation is a common feature of many neurodegenerative diseases, which often enhances neuronal loss and fosters a dysfunctional neuron microglia-astrocyte crosstalk that, in turn, maintains microglial cells into a perniciously reactive state. The molecular components that mediates this critical communication are however non fully explored. Here, we have asked whether Secreted-Frizzled-Related-Protein 1 (SFRP1), a multifunctional regulator of cell to cell communication, is part of the cellular crosstalk underlying neuroinflammation. We show that in mouse models of acute and chronic neuroinflammation, astrocyte-derived SFRP1 is sufficient to promote microglial activation and to enhance their response to damage, sustaining a chronic inflammatory state. SFRP1 allows the upregulation of components of Hypoxia Induced Factors-dependent inflammatory pathway and, to a much lower extent, of those downstream of the Nuclear Factor-kappaB. We thus propose that SFRP1 acts as a critical astrocyte to microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation present in several neurodegenerative diseases.