2. Academic Validation
  3. The chloride intracellular channel 1 (CLIC1) is essential for microglial morphodynamics and neuroinflammation

The chloride intracellular channel 1 (CLIC1) is essential for microglial morphodynamics and neuroinflammation

  • Sci Adv. 2025 Oct 24;11(43):eads9181. doi: 10.1126/sciadv.ads9181.
Ali Rifat 1 2,  Tom Bickel 1,  Patricia Kreis 3,  Thorsten Trimbuch 1,  Julia Onken 4,  Andranik Ivanov 5,  Giulia Albertini 6 7,  Dieter Beule 5,  Michele Mazzanti 8,  Harpreet Singh 9,  Britta J Eickholt 3,  Bart De Strooper 6 7 10,  Jörg R P Geiger 1,  Christian Madry 1
Affiliations

Affiliations

  • 1 Institute of Neurophysiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • 2 Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • 3 Institute of Biochemistry and Molecular Biology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.
  • 4 Department of Neurosurgery, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
  • 5 Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 6 Centre for Brain and Disease Research, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
  • 7 Department of Neurosciences and Leuven Brain Institute, KU Leuven, Leuven, Belgium.
  • 8 Laboratory of Cellular and Molecular Physiology, Department of Biosciences, University of Milan, Via Celoria 26, I-20133 Milano, Italy.
  • 9 Department of Physiology and Cell Biology, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • 10 UK Dementia Research Institute at UCL, University College London, London, UK.
PMID: 41124273 DOI: 10.1126/sciadv.ads9181
Abstract

Microglial functions rely on their morphodynamic versatility and inflammatory response, yet the molecular determinants, particularly ion channels and receptors, remain poorly understood. Here, we identify chloride intracellular channel 1 (CLIC1), a protein known to exist in both soluble and membrane-associated forms, as highly enriched in human and murine microglia, with minimal expression in Other brain cells. Acute blockade or genetic deletion of CLIC1 markedly attenuates microglial surveillance by reducing ramification and motility, without affecting chemotaxis. This phenotype is recapitulated in xenografted human microglia and human brain tissue. Mechanistically, CLIC1 effects involve interactions with actin-binding ezrin, radixin, and moesin (ERM) proteins, suggesting a role in linking the plasma membrane to the Cytoskeleton. Contrary to its name, CLIC1 functions are chloride-independent and thus unlikely to reflect ion channel activity. This is supported by patch-clamp electrophysiology revealing lack of chloride conductance in surveillant microglia. Following ATP-evoked activation, CLIC1 blockade strongly suppresses NLRP3-dependent interleukin-1β release, suggesting therapeutic potential against neuroinflammation.

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