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.
Highlights
The authors purified the zebrafish counterparts of the human chemokine (C-X-C motif) ligand 11 (CXCL11) family and demonstrated that two of these are inducible by infection and recruit macrophages via the CXC chemokine receptor 3 (CXCR3) receptor in the zebrafish model
We report on the function of CXCR3 signaling in macrophage recruitment to infection foci and in the early establishment of mycobacterial granulomas
We found that the Cxcr3.2 receptor, one of the three zebrafish homologs of human CXCR3, interacts with infectioninducible zebrafish homologs of the CXCL11 ligand family and is required for the mobilization of macrophages to different pathogens, such as locally delivered M. marinum or S. typhimurium
Summary
CXCL9 [ known as MIG (monokineinduced by IFN-γ)], CXCL10 [IP-10 (IFN-γ-inducible protein 10)] and CXCL11 [I-TAC (T cell α chemoattractant)] are IFN-inducible chemokines and mediate recruitment of T cells, natural killer (NK) cells and monocytes/macrophages at the infection site, predominantly through their cognate G-protein coupled receptor, CXCR3 (Janatpour et al, 2001; Loetscher et al, 1996) This signaling axis has been implicated in several physiological activities, including maturation of T cells and vasculogenesis (Liu et al, 2005; Zhou et al, 2010). Recent studies have demonstrated that CXCR3 plays an important role in directing macrophage activities, both under physiological and under pathological conditions (Cuenca et al, 2011; Kakuta et al, 2012; Oghumu et al, 2014; Zhou et al, 2010)
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