Rifat, Ali;
Bickel, Tom;
Kreis, Patricia;
Trimbuch, Thorsten;
Onken, Julia;
Ivanov, Andranik;
Albertini, Giulia;
... Madry, Christian; + view all
(2025)
The chloride intracellular channel 1 (CLIC1) is essential for microglial morphodynamics and neuroinflammation.
Science Advances
, 11
(43)
, Article eads9181. 10.1126/sciadv.ads9181.
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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.
| Type: | Article |
|---|---|
| Title: | The chloride intracellular channel 1 (CLIC1) is essential for microglial morphodynamics and neuroinflammation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciadv.ads9181 |
| Publisher version: | https://doi.org/10.1126/sciadv.ads9181 |
| Language: | English |
| Additional information: | Copyright © 2025 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Microglia, Chloride Channels, Animals, Humans, Mice, Microfilament Proteins, Neuroinflammatory Diseases, Cytoskeletal Proteins, Mice, Knockout, NLR Family, Pyrin Domain-Containing 3 Protein, Membrane Proteins, Interleukin-1beta, Inflammation, Chlorides |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10216323 |
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