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Lymph Nodes High Endothelial Venule Expansion in Factor A B Cell-Derived Vascular Endothelial Growth Factor A Promotes Lymphangiogenesis and High Endothelial Venule Expansion in Lymph Nodes This information is current as of September 26, 2021. Binita Shrestha, Teruto Hashiguchi, Takashi Ito, Naoki Miura, Kazunori Takenouchi, Yoko Oyama, Ko-ichi Kawahara, Salunya Tancharoen, Yuya Ki-i, Noboru Arimura, Narimasa Yoshinaga, Satoshi Noma, Chandan Shrestha, Takao Nitanda, Shinichi Kitajima, Kimiyoshi Arimura, Masahiro Sato, Taiji Sakamoto and Ikuro Downloaded from Maruyama J Immunol 2010; 184:4819-4826; Prepublished online 22 March 2010; doi: 10.4049/jimmunol.0903063 http://www.jimmunol.org/ http://www.jimmunol.org/content/184/9/4819 Supplementary http://www.jimmunol.org/content/suppl/2010/03/22/jimmunol.090306 Material 3.DC1 References This article cites 38 articles, 15 of which you can access for free at: by guest on September 26, 2021 http://www.jimmunol.org/content/184/9/4819.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology B Cell-Derived Vascular Endothelial Growth Factor A Promotes Lymphangiogenesis and High Endothelial Venule Expansion in Lymph Nodes Binita Shrestha,*,1 Teruto Hashiguchi,*,1 Takashi Ito,*,1 Naoki Miura,†,1 Kazunori Takenouchi,* Yoko Oyama,* Ko-ichi Kawahara,* Salunya Tancharoen,* Yuya Ki-i,‡ Noboru Arimura,‡ Narimasa Yoshinaga,‡ Satoshi Noma,x Chandan Shrestha,* Takao Nitanda,{ Shinichi Kitajima,{ Kimiyoshi Arimura,|| Masahiro Sato,# Taiji Sakamoto,‡ and Ikuro Maruyama* Vascular endothelial growth factor A (VEGF-A) is a prominent growth factor for both angiogenesis and lymphangiogenesis. Recent Downloaded from studies have shown the importance of VEGF-A in enhancing the growth of lymphatic endothelial cells in lymph nodes (LNs) and the migration of dendritic cells into LNs. VEGF-A is produced in inflamed tissues and/or in draining LNs, where B cells are a possible source of this growth factor. To study the effect of B cell-derived VEGF-A, we created transgenic mice (CD19Cre/hVEGF-Afl) that express human VEGF-A specifically in B cells. We found that the human VEGF-A produced by B cells not only induced lymphangiogenesis in LNs, but also induced the expansion of LNs and the development of high endothelial venules. Contrary to our expectation, we observed a significant decrease in the Ag-specific Ab production postimmunization with OVA and in the http://www.jimmunol.org/ proinflammatory cytokine production postinoculation with LPS in these mice. Our findings suggest immunomodulatory effects of VEGF-A: B cell-derived VEGF-A promotes both lymphangiogenesis and angiogenesis within LNs, but then suppresses certain aspects of the ensuing immune responses. The Journal of Immunology, 2010, 184: 4819–4826. ost defense against infection requires the integrated which results in the upregulation of CCR7. Expression of CCR7 function of both the innate and the adaptive immune allows the DCs to enter draining lymphatic vessels that express the H systems. Innate immune responses, which represent the CCR7 ligands CCL21 and CCL19 (2). On reaching the draining front line of the immune system, are elicited by a variety of cell lymph nodes (LNs), the DCs interact with T and B cells, thus types, including granulocytes, macrophages, mast cells, NK cells, inducing adaptive immune responses. by guest on September 26, 2021 and dendritic cells (DCs). DCs are the professional APCs that form Lymphatic vessels are essential for transporting tissue fluid, the bridge between innate and adaptive immune responses (1). DCs extravasated plasma proteins, and cells back to the blood circu- process material from invading pathogens and damaged tissues, lation (3). Lymphatic vessels contribute to the immune surveil- lance of the body by transporting Ag-bearing DCs from peripheral tissues to the regional LNs, where they present Ags to lympho- *Department of Laboratory and Vascular Medicine, ‡Department of Ophthalmology, cytes. Congenital or acquired dysfunction of lymphatic vessels and ||Department of Neurology and Geriatrics, Graduate School of Medical and leads to chronic swelling, adipose degeneration, immune dys- Dental Sciences, †Laboratory of Diagnostic Imaging, Department of Veterinary Med- icine, Faculty of Agriculture, and #Section of Gene Expression Regulation, Frontier function, and susceptibility to infection (3). Science Research Center, Kagoshima University; and xDivision of Respiratory Med- Lymphatic vessels are not simply inert drainage ducts; rather, { icine, Respiratory and Stress Care Center and Division of Surgical Pathology, Ka- they are actively involved in many physiologic and pathologic goshima University Medical and Dental Hospital, Kagoshima, Japan 1 processes. For example, remodeling of lymphatic vessels by tumor- B.S., T.H., T.I., and N.M. contributed equally to this work. derived lymphangiogenic factors actively promotes cancer metas- Received for publication September 23, 2009. Accepted for publication February 17, tasis (4–6). Lymphatic vessels are also remodeled in various in- 2010. flammatory conditions (7), and these remodeled vessels promote This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (C: 17590888, C: 13670659, C: inflammation (8–10). Recent studies have revealed that lymphatic 15590901, and B: 19390156) and by a grant from Mitsubishi Pharma Research vessel growth (lymphangiogenesis) is regulated by vascular en- Foundation, Japan (to T.H.). dothelial growth factor (VEGF)-C and -D via their receptor, Address correspondence and reprint requests to Dr. Teruto Hashiguchi, Department of VEGFR-3 (10, 11). In addition, VEGF-A and its receptor, VEGFR-2, Laboratory and Vascular Medicine, Cardiovascular and Respiratory Disorders, Kagoshi- ma University Graduate School of Medical and Dental Sciences, 8-35-1, Sakuragaoka, also play an important role in lymphangiogenesis, especially in Kagoshima 890-8520, Japan. E-mail address: [email protected] the enlargement of lymphatic vessels (6, 12, 13). The online version of this article contains supplemental material. During inflammatory conditions, remodeling of lymphatic vessels Abbreviations used in this paper: CAG, CMV enhancer/chicken b-actin promoter; occurs not only in inflamed peripheral tissues, but also in the CAT, chloramphenicol acetyltransferase; DC, dendritic cell; EGFP, enhanced green regional LNs. Expansion of lymphatic vessels within LNs is impor- fluorescent protein; HEV, high endothelial venule; hVEGF-A, human vascular endo- thelial growth factor A; LN, lymph node; LYVE-1, lymphatic vessel endothelial tant because it enhances the mobilization of DCs to the draining hyaluronan receptor-1; mVEGF-A: mouse vascular endothelial growth factor A; LNs (14). Expansion of lymphatic vessels within LNs can be locally ND, not detected; p-hVEGF-A, plasmid of human vascular endothelial growth factor controlled by lymphangiogenic factors released within the LNs A; Tg, transgenic; VEGF-A, vascular endothelial growth factor A; WT, wild-type. (14, 15) or remotely controlled by factors released in the peripheral Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 tissues (16). In the former case, this process depends upon the www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903063 4820 IMMUNOMODULATORY EFFECTS OF VEGF-A presence of B cells within the LNs (14, 15). B cells in inflamed LNs Immunohistochemical staining express VEGF-A and can be stimulated to secrete VEGF-A in vitro For immunohistochemistry, paraffin sections were heated in a microwave (14), suggesting the involvement of B cell-derived VEGF-A in oven for 20 min, dewaxed in xylene, and rehydrated through a graded series lymphangiogenesis and DC mobilization. However, the exact role of ethanol solutions. Endogenous peroxidase activity was blocked by of B cell-derived VEGF-A in vivo is still unknown. incubation with 0.3% hydrogen peroxide in absolute methanol for 15 min at In this study, we investigated the effect of B cell-derived VEGF- room temperature. Ag epitopes were heat-retrieved in Antigen Unmasking Cre fl Solution (Vector Laboratories, Burlingame, CA). Samples were then in- A in vivo using CD19 /hVEGF-A mice that express human cubated overnight at 4˚C with primary Abs: rabbit polyclonal anti- VEGF-A (hVEGF-A) specifically in B cells. We found that these lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) (1/500 mice had enlarged LNs, with expanded lymphatic vessels and dilution; Upstate Biotechnology, Temecula, CA), rabbit polyclonal anti- increased high endothelial venules (HEVs), even when they were mouse PECAM-1 (M-20) (1/500 dilution; Santa Cruz Biotechnology, Santa Cruz, CA), rat monoclonal anti-mouse CD45R/B220
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