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16.06.2017 | Original Paper | Ausgabe 4/2017

Angiogenesis 4/2017

CXCL10 suppression of hem- and lymph-angiogenesis in inflamed corneas through MMP13

Angiogenesis > Ausgabe 4/2017
Nan Gao, Xiaowei Liu, Jiayin Wu, Juan Li, Chen Dong, Xinyi Wu, Xiao Xiao, Fu-Shin X. Yu
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Electronic supplementary material

The online version of this article (doi:10.​1007/​s10456-017-9561-x) contains supplementary material, which is available to authorized users.


Though not present in the normal adult cornea, both hem- and lymph-angiogenesis can be induced in this tissue after an inflammatory, infectious, or traumatic insult. We previously showed that the chemokine CXCL10 plays a key role in eradicating invading Candida (C.) albicans in C57BL6 mouse corneas. However, even after the clearance of pathogens, infection-induced inflammation and angiogenesis continue to progress in the cornea. The aim of this study is define the role of CXCL10 as a major angiostatic factor in modulating cornea angiogenesis in B6 mouse corneas under pathogenic conditions. We showed that epithelial expression of CXCL10, driven by AAV9 vector, suppressed both infection- and inflammation-induced hem and lymph angiogenesis, whereas the neutralization of CXCL10 as well as its receptor CXCR3 greatly promoted these processes. The inhibitory effect of CXCL10 was unrelated to its antimicrobial activity, but through the suppression of the expression of many angiogenic factors, including VEGFa and c, and MMP-13 in vivo. Inhibition of MMP13 but not TIMPs, attenuated suture-induced neovascularization but had no effects on CXCL10 expression. Strikingly, topical application of CXCL10 post-C. albicans infection effectively blocked both hem- and lymph-angiogenesis and preserved the integrity of sensory nerves in the cornea. Taken together, CXCL10 has strong inhibitory effects on neovascularization, whereas MMP13 is required for neovascularization in C. albicans-infected corneas and the local application of CXCL10 or MMP13 inhibitors, alone or as adjuvant therapy, may target hem- and lymph-angiogenesis in the inflamed corneas.

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sFig. 1 CXCL10-CXCR3-mediated signaling is required for CA clearance in the cornea. The CXCL10 or CXCR3 neutralizing antibodies, along with control rabbit IgG, were injected into subconjunctival spaces 4 h prior to AAV-GFP or CXCL10 infection for 2 weeks, followed by CA inoculation. At 1dpi, the eyes were enucleated and subjected to fungal culture by colony counting. The results are presented as the number of CFU per cornea. A nonparametric Mann–Whitney U test was performed to compare each flagellin pretreatment to the PBS group (*p < 0.05, **p < 0.01, n = 5). Results are representative of three independent experiments (TIFF 5999 kb)
sFig. 2 CXCL10 induce apoptosis of vessel endothelial cells in vitro. Human CECs were starved overnight and transfected with 1.5X1011 cfu of AAV2-GFP or -CXCL10. At day 3 post infection, fresh medium were replaced and cells were further cultured for 1 day and media collected as conditioned media for the culture of hBRVECs or primary lymphatic endothelial cells (LECs) which were photographed by ZEISS Axiovert 200 microscope (A) or subjected to Annexin V and propidium iodide staining for apoptotic and necrotic cells (B). (TIFF 9321 kb)
sFig. 3 Proteome array analysis of angiogenic growth factors. A. Proteome Profiler arrays probed with extracts of AAV9-CXCL10 or AAV9-GFP transfected or anti-CXCL10 treated corneas 4 days post C. albicans infection; numbers indicate individual factors with detectable differences among 4 conditions. B. Average protein expression levels of two spots on an array were measured by using by Photoshop. (TIFF 17707 kb)
sFig. 4 The colocalization of CD11c and CXCR3. C57BL/6 mouse corneas (n = 3 for each condition) were infected with injected AAV-GFP or CXCL10 for 2 weeks, followed by sutured as described in Figure 3, then stained with CXCR3 and CD31 (TIFF 27688 kb)
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