Alkali injury–induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation
Zheng Liu, Keli Liu, Shunhua Shi, Xun Chen, Xinyu Gu, Weifa Wang, Keli Mao, Rukeye Yibulayi, Wanwen Wu, Lei Zeng, Weibin Zhou, Xiaofeng Lin, Feng Zhang, Bingsheng Lou
Zheng Liu, Keli Liu, Shunhua Shi, Xun Chen, Xinyu Gu, Weifa Wang, Keli Mao, Rukeye Yibulayi, Wanwen Wu, Lei Zeng, Weibin Zhou, Xiaofeng Lin, Feng Zhang, Bingsheng Lou
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Research Article Immunology Ophthalmology

Alkali injury–induced pathological lymphangiogenesis in the iris facilitates the infiltration of T cells and ocular inflammation

Abstract

Inflammatory lymphangiogenesis is intimately linked to immune regulation and tissue homeostasis. However, current evidence has suggested that classic lymphatic vessels are physiologically absent in intraocular structures. Here, we show that neolymphatic vessels were induced in the iris after corneal alkali injury (CAI) in a VEGFR3-dependent manner. Cre-loxP–based lineage tracing revealed that these lymphatic endothelial cells (LECs) originate from existing Prox1+ lymphatic vessels. Notably, the ablation of iridial lymphangiogenesis via conditional deletion of VEGFR3 alleviated the ocular inflammatory response and pathological T cell infiltration. Our findings demonstrate that iridial neolymphatics actively participate in pathological immune responses following injury and suggest intraocular lymphangiogenesis as a valuable therapeutic target for the treatment of ocular inflammation.

Authors

Zheng Liu, Keli Liu, Shunhua Shi, Xun Chen, Xinyu Gu, Weifa Wang, Keli Mao, Rukeye Yibulayi, Wanwen Wu, Lei Zeng, Weibin Zhou, Xiaofeng Lin, Feng Zhang, Bingsheng Lou

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Figure 1

Corneal alkali injury (CAI) induces iridial lymphangiogenesis.

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Corneal alkali injury (CAI) induces iridial lymphangiogenesis. (A) Schem...
(A) Schematic showing experimental timeline of CAI and analysis of lymphangiogenesis in the cornea and iris on days 0, 14, 16, 21, and 28. (B) Immunofluorescence staining of LYVE1+ lymphatic vessels in cornea and iris tissue whole mounts from mice at the indicated days after CAI or sham treatment. The CAI or sham treatment was done by placing a 2 mm round filter paper infiltrated with 0.5 μL of 1 M sodium hydroxide solution (CAI) or PBS (sham) on the cornea for 60 seconds. Note that sparse LYVE1+ neolymphatics initially formed in the iris whole mounts on day 16 after CAI and underwent expansion thereafter (see arrows). Scale bar: 1 mm. (C) Quantitation of Lyve1+ lymphatic covered area in the cornea and iris from mice received CAI or sham treatment at the indicated time points following CAI. All data are mean ± SEM. n = 10 mice per group. Each dot represents 1 mouse. *P < 0.05, **P < 0.01, ***P < 0.001. Mann-Whitney U test. (D) Characterization of expression of common lymphatic endothelial cell (LEC) markers (LYVE1, Prox1, VEGFR3, and CD31) in CAI-induced iridial neolymphatics in mice, compared with sham control mice, on day 28 after the treatment. Scale bars: 1 mm and 100 μm. (E) VE-cadherin and Lyve1 staining of the iris tissue whole mounts from mice on day 28 after the CAI or sham treatment. Scale bars: 100 μm and 50 μm.