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 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.
Highlights
Macrophages are specialized motile cells that mediate the innate immune response to pathogens, initiate inflammation, present antigens, regulate tissue repair, and have diverse functions in developmental processes (Ginhoux et al, 2016)
We investigated the link between chemotactic signaling and lysosomal function in vivo using a cxcr3.2 mutant zebrafish line deficient in a macrophage-attractant chemokine receptor homologous to human CXCR3 (Torraca et al, 2015)
Supporting the connection between Cxcr3 chemotactic signaling and lysosomal function, we found that expression of dominant-negative Tfec phenocopied the infection resistance of cxcr3.2 mutants, while their enhanced microbicidal capacity was counteracted by tfec overexpression
Summary
Macrophages are specialized motile cells that mediate the innate immune response to pathogens, initiate inflammation, present antigens, regulate tissue repair, and have diverse functions in developmental processes (Ginhoux et al, 2016). Macrophages differentially express chemokine receptors to sense extracellular cues that direct them to inflammatory sites (Charo and Ransohoff, 2006; Rot and von Andrian, 2004). Following chemotactic stimulation, these cells acquire a polarized phenotype characterized by clearly identifiable lamellipodia (leading edge) and a uropod (rear edge) that involves both the contractile machinery of the cell and the intracellular vesicle trafficking system (Colvin et al, 2010). Processes linking cell motility and lysosomal function are only partially understood, and the effect of chemokine signaling on lysosomal function during inflammatory processes in vivo remains largely unknown
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