PMID- 35931408 OWN - NLM STAT- MEDLINE DCOM- 20221212 LR - 20221217 IS - 1937-5913 (Electronic) IS - 1542-0124 (Linking) VI - 26 DP - 2022 Oct TI - Alleviating experimental allergic eye disease by inhibiting pro-lymphangiogenic VEGFR3 signal. PG - 1-12 LID - S1542-0124(22)00055-6 [pii] LID - 10.1016/j.jtos.2022.07.002 [doi] AB - PURPOSE: Ocular allergy leads to acute and chronic inflammation that may deteriorate the conjunctiva and other ocular tissue. The conjunctiva is covered with abundant lymphatic vessels but how the conjunctival lymphatic system patriciates in the development of allergic eye disease (AED) remains to be elucidated. METHODS AND RESULTS: By using ovalbumin (OVA)+pertussis toxin (PTX) as a sensitizer followed by daily OVA challenges, we induced optimized AED manifestations in mice. We show that conjunctival lymphatics underwent significant expansion after 28 days of chronic OVA challenge, and this process can be prevented by inducible genetic ablation of lymphatic Vegfr3. Through transcriptomic profile analysis in combination with histopathological examinations, we found that pro-lymphangiogenic VEGFR3 signal promoted allergy-induced activation of T helper 2 (Th2) type immune responses, including antigen presentation, and Th2 cells, B cells and mast cell-related pathways in the conjunctiva, thereby critically contributing to the immunoglobulin E (IgE) production and AED manifestations. As a result, ocular allergy can be alleviated by genetic inhibition of lymphatic Vegfr3. Interestingly, pro-lymphangiogenic VEGFR3 signal did not appear to affect the obstruction of meibomian glands (MGs) or the activation of Th17 type and neutrophil pathways that are associated with AED. CONCLUSIONS: These data reveal the key role of pro-lymphangiogenic VEGFR3 signaling in the development of AED and provide experimental evidence that VEGFR3 inhibition may be useful in treating ocular allergy in patients. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Lou, Bingsheng AU - Lou B AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Wu, Wanwen AU - Wu W AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Zeng, Lei AU - Zeng L AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Zhou, Weibin AU - Zhou W AD - Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510080, China. FAU - Zhang, Xuan AU - Zhang X AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Zhou, Xuetong AU - Zhou X AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Liu, Zheng AU - Liu Z AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Liu, Keli AU - Liu K AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Gu, Xinyu AU - Gu X AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Chen, Xun AU - Chen X AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Wang, Yeqi AU - Wang Y AD - Key Laboratory for Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, 400044, China; State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400044, China. FAU - Chen, Yangxin AU - Chen Y AD - Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510080, China. FAU - Gao, Xinbo AU - Gao X AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. FAU - Zhang, Feng AU - Zhang F AD - State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China. Electronic address: zhangfeng@mail.sysu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220802 PL - United States TA - Ocul Surf JT - The ocular surface JID - 101156063 RN - 9006-59-1 (Ovalbumin) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-3) SB - IM MH - Animals MH - Mice MH - Disease Models, Animal MH - *Eye Diseases MH - *Hypersensitivity MH - Lymphangiogenesis/physiology MH - Ovalbumin MH - Vascular Endothelial Growth Factor Receptor-3/metabolism OTO - NOTNLM OT - Allergic eye disease OT - CD4(+) T cell OT - Lymph node OT - Lymphatics OT - Vegfr3 EDAT- 2022/08/06 06:00 MHDA- 2022/12/15 06:00 CRDT- 2022/08/05 19:28 PHST- 2021/12/29 00:00 [received] PHST- 2022/06/29 00:00 [revised] PHST- 2022/07/18 00:00 [accepted] PHST- 2022/08/06 06:00 [pubmed] PHST- 2022/12/15 06:00 [medline] PHST- 2022/08/05 19:28 [entrez] AID - S1542-0124(22)00055-6 [pii] AID - 10.1016/j.jtos.2022.07.002 [doi] PST - ppublish SO - Ocul Surf. 2022 Oct;26:1-12. doi: 10.1016/j.jtos.2022.07.002. Epub 2022 Aug 2.