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Chloride transporter ClC-7 is essential for phagocytic clearance by microglia.
Journal of Cell Science 2024 January 32
Microglia, professional phagocytic cells of the brain, rely upon the appropriate activation of lysosomes to execute their immune and clearance functions. Lysosomal activity is, in turn, modulated by a complex network of over 200 membrane and accessory proteins that relay extracellular cues to these key degradation centers. The ClC-7 chloride-proton antiporter is localized to the endolysosomal compartments and mutations in clcn7 lead to osteopetrosis and neurodegeneration. Although the functions of ClC-7 have been extensively investigated in osteoclasts and neurons, its role in microglia in vivo remains largely unexamined. Here we show that microglia and embryonic macrophages in clcn7 mutants cannot effectively process extracellular debris in the form of apoptotic cells and beta-amyloid. Despite these functional defects, microglia develop normally in clcn7 mutants and display normal expression of endosomal and lysosomal markers. We also find that mutants for ostm1, which encodes the beta-subunit of ClC-7, have a phenotype strikingly similar to that of clcn7. Together, our observations uncover a previously unappreciated role of ClC-7 in microglia and contribute to the understanding of the neurodegenerative phenotypes that accompany mutations in this channel.
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