SFRP1 modulates astrocyte‐to‐microglia crosstalk in acute and chronic neuroinflammation

Neuroinflammation is a common feature of many neurodegenerative diseases. It fosters a dysfunctional neuron–microglia–astrocyte crosstalk that, in turn, maintains microglial cells in a perniciously reactive state that often enhances neuronal damage. The molecular components that mediate this critical communication are not fully explored. Here, we show that secreted frizzled‐related protein 1 (SFRP1), a multifunctional regulator of cell‐to‐cell communication, is part of the cellular crosstalk underlying neuroinflammation. In mouse models of acute and chronic neuroinflammation, SFRP1, largely astrocyte‐derived, promotes and sustains microglial activation, and thus a chronic inflammatory state. SFRP1 promotes the upregulation of components of the hypoxia‐induced factor‐dependent inflammatory pathway and, to a lower extent, of those downstream of the nuclear factor‐kappa B. We thus propose that SFRP1 acts as an astrocyte‐to‐microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation in several neurodegenerative diseases.