The chloride intracellular channel 1 (CLIC1) is essential for microglial morphodynamics and neuroinflammation
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.
Authors
- Michele Mazzanti (ORCID: https://orcid.org/0000-0002-1819-3811)
- Thorsten Trimbuch (ORCID: https://orcid.org/0000-0001-7512-8955)
- Christian Madry (ORCID: https://orcid.org/0000-0002-0522-7197)
- Andranik Ivanov (ORCID: https://orcid.org/0000-0002-4824-1925)
- Giulia Albertini (ORCID: https://orcid.org/0000-0002-8215-2432)
- Bart De Strooper (ORCID: https://orcid.org/0000-0001-5455-5819)
- Patricia Kreis (ORCID: https://orcid.org/0000-0002-1702-4805)
- Ali Rifat (ORCID: https://orcid.org/0000-0001-5801-4358)
- Harpreet Singh (ORCID: https://orcid.org/0000-0002-6135-1897)
- Dieter Beule (ORCID: https://orcid.org/0000-0002-3284-0632)
- Britta J. Eickholt (ORCID: https://orcid.org/0000-0001-7873-8687)
- Jörg R. P. Geiger (ORCID: https://orcid.org/0000-0001-9552-4322)
- Julia Onken (ORCID: https://orcid.org/0000-0002-2859-4395)
- Tom Bickel
Institutions
- University of Milan (IT)
- Vlaams Instituut voor Biotechnologie (BE)
- The Ohio State University Wexner Medical Center (US)
- Humboldt-Universität zu Berlin (DE)
- UK Dementia Research Institute (GB)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University College London (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1126/sciadv.ads9181
- Citations
- 2
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.68