1. Disruption of Cxcr3 chemotactic signaling alters lysosomal function and renders macrophages more microbicidal.
- Author
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Sommer F, Torraca V, Xie Y, In 't Veld AE, Willemse J, and Meijer AH
- Subjects
- Animals, Animals, Genetically Modified, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors immunology, Cell Tracking, Chemotaxis genetics, Chemotaxis immunology, Embryo, Nonmammalian, Gene Expression Profiling, Gene Expression Regulation, Genes, Reporter, Larva immunology, Larva microbiology, Luminescent Proteins genetics, Luminescent Proteins immunology, Lysosomes metabolism, Lysosomes microbiology, Lysosomes ultrastructure, Macrophage Activation, Macrophages microbiology, Macrophages ultrastructure, Mutation, Mycobacterium Infections immunology, Mycobacterium Infections microbiology, Mycobacterium marinum immunology, Mycobacterium marinum pathogenicity, Receptors, CXCR3 immunology, Sequence Analysis, RNA, Signal Transduction genetics, Zebrafish immunology, Zebrafish microbiology, Zebrafish Proteins immunology, Red Fluorescent Protein, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Lysosomes immunology, Macrophages immunology, Mycobacterium Infections genetics, Receptors, CXCR3 genetics, Signal Transduction immunology, Zebrafish genetics, Zebrafish Proteins genetics
- Abstract
Chemotaxis and lysosomal function are closely intertwined processes essential for the inflammatory response and clearance of intracellular bacteria. We used the zebrafish model to examine the link between chemotactic signaling and lysosome physiology in macrophages during mycobacterial infection and wound-induced inflammation in vivo. Macrophages from zebrafish larvae carrying a mutation in a chemokine receptor of the Cxcr3 family display upregulated expression of vesicle trafficking and lysosomal genes and possess enlarged lysosomes that enhance intracellular bacterial clearance. This increased microbicidal capacity is phenocopied by inhibiting the lysosomal transcription factor EC, while its overexpression counteracts the protective effect of chemokine receptor mutation. Tracking macrophage migration in zebrafish revealed that lysosomes of chemokine receptor mutants accumulate in the front half of cells, preventing macrophage polarization during chemotaxis and reaching sites of inflammation. Our work shows that chemotactic signaling affects the bactericidal properties and localization during chemotaxis, key aspects of the inflammatory response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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