title: The CXCR3-CXCL11 signaling axis mediates macrophage recruitment and dissemination of mycobacterial infection.
abstract: The recruitment of leukocytes to infectious foci depends strongly on the local release of chemoattractant mediators. The human CXC chemokine receptor 3 (CXCR3) is an important node in the chemokine signaling network and is expressed by multiple leukocyte lineages, including T cells and macrophages. The ligands of this receptor originate from an ancestral CXCL11 gene in early vertebrates. Here, we used the optically accessible zebrafish embryo model to explore the function of the CXCR3-CXCL11 axis in macrophage recruitment and show that disruption of this axis increases the resistance to mycobacterial infection. In a mutant of the zebrafish ortholog of CXCR3 (cxcr3.2), macrophage chemotaxis to bacterial infections was attenuated, although migration to infection-independent stimuli was unaffected. Additionally, attenuation of macrophage recruitment to infection could be mimicked by treatment with NBI74330, a high-affinity antagonist of CXCR3. We identified two infection-inducible CXCL11-like chemokines as the functional ligands of Cxcr3.2, showing that the recombinant proteins exerted a Cxcr3.2-dependent chemoattraction when locally administrated in vivo. During infection of zebrafish embryos with Mycobacterium marinum, a well-established model for tuberculosis, we found that Cxcr3.2 deficiency limited the macrophage-mediated dissemination of mycobacteria. Furthermore, the loss of Cxcr3.2 function attenuated the formation of granulomatous lesions, the typical histopathological features of tuberculosis, and led to a reduction in the total bacterial burden. Prevention of mycobacterial dissemination by targeting the CXCR3 pathway, therefore, might represent a host-directed therapeutic strategy for treatment of tuberculosis. The demonstration of a conserved CXCR3-CXCL11 signaling axis in zebrafish extends the translational applicability of this model for studying diseases involving the innate immune system.
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Torraca
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Chao
authors.initials: C
authors.lastname: Cui
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Ralf
authors.initials: R
authors.lastname: Boland
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems, Division Medicinal Chemistry, Faculty of Sciences, VU University, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Jan-Paul
authors.initials: JP
authors.lastname: Bebelman
authors.affiliation: Department of Medical Microbiology and Infection Control, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: van der Sar
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems, Division Medicinal Chemistry, Faculty of Sciences, VU University, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems, Division Medicinal Chemistry, Faculty of Sciences, VU University, De Boelelaan 1105, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: Siderius
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Herman P
authors.initials: HP
authors.lastname: Spaink
authors.affiliation: Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands a.h.meijer@biology.leidenuniv.nl.
authors.forename: Annemarie H
authors.initials: AH
authors.lastname: Meijer
mesh_terms: D000818:Animals; D002465:Cell Movement; D054371:Chemokine CXCL11 / Q000378:metabolism*; D002630:Chemotactic Factors / Q000494:pharmacology; D018389:Codon, Nonsense / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D006099:Granuloma / Q000473:pathology; D006801:Humans; D007814:Larva / Q000254:growth & development; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009164:Mycobacterium Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D010586:Phagocytes / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology / Q000382:microbiology; D029961:Zebrafish Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D054371:Chemokine CXCL11; D002630:Chemotactic Factors; D018389:Codon, Nonsense; D054367:Receptors, CXCR3; D011994:Recombinant Proteins; D029961:Zebrafish Proteins
keywords: CXCL11; CXCR3; Chemokine; Immunology; Macrophage biology; Mycobacterium; Tuberculosis; Zebrafish