SFRP1 modulates astrocyte‐to‐microglia crosstalk in acute and chronic neuroinflammation. (27th September 2021)

• Record Type: Journal Article
• Authors: Rueda‐Carrasco, Javier; Martin‐Bermejo, María Jesús; Pereyra, Guadalupe; Mateo, María Inés; Borroto, Aldo; Brosseron, Frederic; Kummer, Markus P; Schwartz, Stephanie; López‐Atalaya, José P; Alarcon, Balbino; Esteve, Pilar; Heneka, Michael T; Bovolenta, Paola
• Is Part Of: EMBO reports. Volume 22:Number 11(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-09-27
• Subjects: activated microglia -- Alzheimer's disease -- HIF pathway -- multiple sclerosis -- reactive astrocytes; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051696
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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. Synopsis: In response to neuroinflammation, astrocytes secrete more SFRP1 protein. SFRP1 enhances glial activation and microglia responses by sustaining robust expression of the down‐stream targets of the HIF pathway. Astrocytes produce SFRP1 in response to neuroinflammation. Increased SFRP1 levels are sufficient to trigger and sustain glial cell activation. Astrocyte‐derived SFRP1 enhances the response of microglial cells to damage. SFRP1 is required for robust microglial expression of down‐stream targets of HIF transcription factors. Abstract : In response to neuroinflammation, astrocytes secrete more SFRP1 protein. SFRP1 enhances glial activation and microglia responses by sustaining robust expression of the down‐stream targets of the HIF pathway.