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

EMBO Rep. 2021 Nov 4;22(11):e51696. doi: 10.15252/embr.202051696. Epub 2021 Sep 27.


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.

Keywords: Alzheimer's disease; HIF pathway; activated microglia; multiple sclerosis; reactive astrocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes*
  • Inflammation / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Microglia* / metabolism
  • Neuroinflammatory Diseases


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Sfrp1 protein, mouse
  • WD repeat containing planar cell polarity effector