Abstract
CXC chemokine receptor 4 plays a critical role in chemotaxis and leukocyte differentiation. Furthermore, there is increasing evidence that links this receptor to angiogenesis. Using the well-established zebrafish-Mycobacterium marinum model for tuberculosis, angiogenesis was recently found to be important for the development of cellular aggregates called granulomas that contain the mycobacteria and are the hallmark of tuberculosis disease. Here, we found that initiation of the granuloma-associated proangiogenic programme requires CXCR4 signalling. The nascent granulomas in cxcr4b-deficient zebrafish embryos were poorly vascularised, which in turn also delayed bacterial growth. Suppressed infection expansion in cxcr4b mutants could not be attributed to an overall deficient recruitment of leukocytes or to different intramacrophage bacterial growth rate, as cxcr4b mutants displayed similar microbicidal capabilities against initial mycobacterial infection and the cellular composition of granulomatous lesions was similar to wildtype siblings. Expression of vegfaa was upregulated to a similar extent in cxcr4b mutants and wildtypes, suggesting that the granuloma vascularisation phenotype of cxcr4b mutants is independent of vascular endothelial growth factor.
Highlights
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and this disease typically manifests by the formation of aggregates of infected and non-infected immune cells that are known as granulomas
Our findings suggest that cxcr4b mutation affects granuloma expansion by primarily affecting the initiation of the angiogenesis programme, and the difference in infection burden appears to be the consequence, rather than the cause, of impaired angiogenic support of granuloma formation
Since the angiogenesis response to mycobacterial infection was found to coincide with local induction of vegfaa[25] and mammalian CXCR4 has been linked to a transcriptional regulation of VEGFA13, we addressed whether cxcr4b affected granuloma-induced angiogenesis by exerting a similar transcriptional control on vegfaa expression in our model
Summary
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and this disease typically manifests by the formation of aggregates of infected and non-infected immune cells that are known as granulomas. Mycobacterium marinum (Mm), a close relative of Mtb, causes a disease that recapitulates significant aspects of human TB, which include the formation of necrotising granulomas and the initiation of specific transcriptional and morphological changes in Mycobacterium-infected macrophages[26,27,28]. It was recently found that Mm can induce granuloma-associated angiogenesis and that initiation of this programme coincides with local induction of hypoxia and expression of the proangiogenic factor vegfaa[25]. The presence of macrophages was strictly necessary for mycobacterial-induced vegfaa expression and initiation of granuloma vascularisation. We show that Cxcr4b-deficient zebrafish larvae display an attenuated induction of the angiogenic programme at the nascent granulomas. Vegfaa was still expressed in cxcr4b deficient larvae, despite the lack of granuloma vascularisation. Our study indicates that Cxcr4b-mediated signalling is required to mediate the full angiogenesis response to mycobacterial infections, and that suppression of pathological angiogenesis with CXCR4 blockers might represent an alternative therapeutic strategy to suppress granuloma-angiogenesis without perturbing VEGF signalling
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