[en] 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.
Disciplines :
Neurologie
Auteur, co-auteur :
Rueda-Carrasco, Javier ; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
Martin-Bermejo, María Jesús; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
Pereyra, Guadalupe; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
Mateo, María Inés; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
Borroto, Aldo; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
Brosseron, Frederic ; Neurology, Universitätsklinikum Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Kummer, Markus P; Neurology, Universitätsklinikum Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Schwartz, Stephanie; Neurology, Universitätsklinikum Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
López-Atalaya, José P ; Instituto de Neurociencias, CSIC-UMH, Sant Joan d'Alacant, Spain
Alarcon, Balbino ; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
Esteve, Pilar; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
HENEKA, Michael ; Neurology, Universitätsklinikum Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Bovolenta, Paola ; Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain ; CIBER de Enfermedades Raras (CIBERER), Madrid, Spain
We wish to thank Prof. J Avila, CBM, for providing a breeding pair of the mice, and Dr. Juan Perea, CBM, for help and advice on glial cultures, the CBM image analysis, genomic and cytometric facilities for their support and advice during the course of this study. This work was supported by grants from the Spanish AEI (BFU2013‐43213‐P; BFU2016‐75412‐R with FEDER support and PID2019‐104186RB‐I00), Fundación Tatiana Pérez de Guzmán el Bueno and CIBERER to PB. JRC (BES‐2011‐047189), GP (BES‐2017‐080318) and MIM (BES‐2014‐068797) were supported by FPI fellowships from the AEI. We also acknowledge a CBM Institutional Grant from the Fundación Ramon Areces. CXCR1::GFP 3
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