Disruption of Cxcr3 Chemotactic Signaling Alters Lysosomal Function and Renders Macrophages More Microbicidal

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 mutated in a Cxcr3 family chemokine receptor 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 blocking 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 macrophages to polarize during chemotaxis and reach sites of inflammation. Our work shows that chemotactic signaling affects the bactericidal properties and localization during chemotaxis, key aspects of the inflammatory response.