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 4

Transcriptomic characterization of CAI-treated iris tissues.

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Transcriptomic characterization of CAI-treated iris tissues. (A) Volcano...
(A) Volcano plot showing CAI-induced 2,896 upregulated differentially expressed genes (DEGs) and 2,332 downregulated DEGs in the iris, as revealed by bulk RNA-Seq analysis of iris tissues dissected from VEGFR3fl/fl mice with CAI or sham treatment. (B) KEGG analysis of upregulated DEGs in A. Dot size and color scale intensities represent counts of DEGs and Padj values of the enriched pathways, respectively. (C) Immunostaining images for F4/80, CD206, and CX3CR1 in the iridial tissue regions with or without lymphatic vessel (LV) coverage in CAI-treated VEGFR3fl/fl mice. Arrows and arrowheads indicate CX3CR1hi and CX3CR1lo macrophages, respectively. Scale bar: 50 μm. (D) Quantification of CD206+ (M2) macrophage counts out of F4/80+ total macrophage counts in C (n = 7). Data are shown as mean ± SEM. n = 7 mice per group. Each dot represents 1 mouse. ***P < 0.001. Mann-Whitney U test. (E) Quantification of CX3CR1hi and CX3CR1lo subsets in F4/80+ total macrophage population in C. Data are shown as mean ± SEM. n = 7 mice per group. Each dot represents 1 mouse. (F) Venn diagram showing intersection between the upregulated DEGs in the injured VEGFR3fl/fl versus Sham VEGFR3fl/fl mouse groups and the downregulated DEGs in the injured VEGFR3iLECko versus injured VEGFR3fl/fl mouse groups. (G) GO analysis of the overlapping 199 DEGs in F. Dot size and color scale intensities represent counts of DEGs and Padj values of the enriched pathways, respectively.