@article{212839d773c0427790f5c2f14a351e47,
title = "Disruption of Cxcr3 chemotactic signaling alters lysosomal function and renders macrophages more microbicidal",
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.",
keywords = "chemotaxis, infection, inflammation, lysosome, macrophage, mycobacteria, vesicle, zebrafish",
author = "Frida Sommer and Vincenzo Torraca and Yufei Xie and {in {\textquoteleft}t Veld}, {Aliede E.} and Joost Willemse and Meijer, {Annemarie H.}",
note = "Funding Information: The authors thank Georges Lutfalla (University of Montpellier) for the macrophage-specific zebrafish reporter lines and Christopher Mahony (University of Birmingham) for the DN-tfec constructs, Michiel van der Vaart (Leiden University) for advice on time-lapse imaging, and all members of the fish facility team for zebrafish care. F.S. was supported by a fellowship from CONACYT . V.T. was a Marie Curie Fellow in the Initial Training Network FishForPharma ( PITN-GA-2011-289209 ), funded by the 7th Framework Programme of the European Commission . Funding Information: The authors thank Georges Lutfalla (University of Montpellier) for the macrophage-specific zebrafish reporter lines and Christopher Mahony (University of Birmingham) for the DN-tfec constructs, Michiel van der Vaart (Leiden University) for advice on time-lapse imaging, and all members of the fish facility team for zebrafish care. F.S. was supported by a fellowship from CONACYT. V.T. was a Marie Curie Fellow in the Initial Training Network FishForPharma (PITN-GA-2011-289209), funded by the 7th Framework Programme of the European Commission. F.S. designed and performed experiments, analyzed the data, and wrote the manuscript. V.T. designed and performed experiments and analyzed data. A.E.t.V. and Y.X. contributed to the experimental work. J.W. wrote the script for the ?lysosomal distribution? analysis. A.M. supervised the study and reviewed the manuscript. All authors commented on the manuscript and approved the final version. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = apr,
day = "13",
doi = "10.1016/j.celrep.2021.109000",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier BV",
number = "2",
}