The CXCR3/CXCL11 signaling axis mediates macrophage recruitment and dissemination of mycobacterial infection

Torraca, V., Cui, C., Boland, R., Bebelman, J.P., van der Sar, A.M., Smit, M.J., Siderius, M., Spaink, H.P., Meijer, A.H.
Disease models & mechanisms   8(3): 253-69 (Journal)
Registered Authors
Meijer, Annemarie H., Spaink, Herman P., Torraca, Vincenzo, van der Sar, Astrid M.
MeSH Terms
  • Animals
  • Cell Movement
  • Chemokine CXCL11/metabolism*
  • Chemotactic Factors/pharmacology
  • Codon, Nonsense/genetics
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Granuloma/pathology
  • Humans
  • Larva/growth & development
  • Macrophages/drug effects
  • Macrophages/metabolism*
  • Mycobacterium Infections/metabolism*
  • Mycobacterium Infections/microbiology
  • Mycobacterium Infections/pathology
  • Phagocytes/metabolism
  • Receptors, CXCR3/analysis
  • Receptors, CXCR3/antagonists & inhibitors
  • Receptors, CXCR3/genetics
  • Receptors, CXCR3/metabolism*
  • Recombinant Proteins/pharmacology
  • Signal Transduction*
  • Zebrafish/embryology
  • Zebrafish/microbiology
  • Zebrafish Proteins/analysis
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
25573892 Full text @ Dis. Model. Mech.
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, while 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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes