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Jimmunol.1900213.Full.Pdf PEPITEM/Cadherin 15 Axis Inhibits T Lymphocyte Infiltration and Glomerulonephritis in a Mouse Model of Systemic Lupus Erythematosus This information is current as of September 29, 2021. Hidehito Matsubara, Yoshitaka Shimizu, Masaaki Arai, Akira Yamagata, Seigo Ito, Toshihiko Imakiire, Masashi Tsunoda, Hiroo Kumagai and Naoki Oshima J Immunol published online 13 March 2020 http://www.jimmunol.org/content/early/2020/03/12/jimmun Downloaded from ol.1900213 http://www.jimmunol.org/ 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 by guest on September 29, 2021 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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 13, 2020, doi:10.4049/jimmunol.1900213 The Journal of Immunology PEPITEM/Cadherin 15 Axis Inhibits T Lymphocyte Infiltration and Glomerulonephritis in a Mouse Model of Systemic Lupus Erythematosus Hidehito Matsubara,* Yoshitaka Shimizu,† Masaaki Arai,‡ Akira Yamagata,* Seigo Ito,* Toshihiko Imakiire,* Masashi Tsunoda,x Hiroo Kumagai,* and Naoki Oshima* Control of lymphocyte infiltration in kidney is a potential therapeutic strategy for lupus nephritis, considering that control of lymphocyte migration by sphingosine 1 phosphate has been implicated in inflammation-related pathology. The peptide inhibitor of the transendo- thelial migration (PEPITEM)/cadherin (CDH) 15 axis was recently reported to promote sphingosine 1 phosphate secretion. In this study, we investigated whether CDH15 is expressed in the kidney of MRL/lprmiceandwhetherlymphocyteinfiltrationissuppressedbyex- Downloaded from ogenously administered PEPITEM. Mice (18 wk old) were randomized into 4-wk treatment groups that received PEPITEM or PBS encapsulated in dipalmitoylphosphatidylcholine liposomes. Enlargement of the kidney, spleen, and axillary lymph nodes was suppressed by PEPITEM treatment, which also blocked infiltration of double-negative T lymphocytes into the kidney and glomerular IgG/C3 de- position, reduced proteinuria, and increased podocyte density. Immunohistochemical analysis revealed that the PEPITEM receptor CDH15 was expressed on vascular endothelial cells of glomeruli and kidney arterioles, skin, and peritoneum in lupus mice at 22 wk of age but not in 4-wk-old mice. These results suggest that PEPITEM inhibits lymphocyte migration and infiltration into the kidney, http://www.jimmunol.org/ thereby preserving the kidney structure and reducing proteinuria. Thus, PEPITEM administration may be considered as a potential therapeutic tool for systemic lupus erythematosus. The Journal of Immunology, 2020, 204: 000–000. he pathogenesis of systemic lupus erythematosus (SLE), a phosphate (S1P) (7, 8), a lipid mediator derived from sphingolipids. chronic autoimmune disease, is not well understood; how- Tissue and blood concentrations of S1P are important for lymphocyte T ever, various targeted therapeutic agents are being developed infiltration into tissues (9–11), which plays an important role in local (1). It is known that nephritis manifests in MRL/MpJJmsSlc-lpr/lpr inflammation (12, 13). PEPITEM controls lymphocyte rolling, (MRL/lpr) mice with age and is accompanied by T lymphocyte adhesion, and migration under inflammatory conditions (7) and by guest on September 29, 2021 infiltration into the interstitium, vasculitis, and immune complex promotes S1P synthesis in vascular endothelial cells through deposition (2). cadherin (CDH) 15, which is expressed as a receptor on inflam- Lupus nephritis is characterized by infiltration of inflammatory matory vascular endothelial cells. Secreted S1P acts on S1P re- cells into the kidney and formation of immune complexes followed ceptors of surrounding T lymphocytes and blocks the interaction by the release of soluble inflammatory cytokines associated with between lymphocyte function-associated Ag-1 and intracellular tissue injury. The local adaptive immune response further amplifies adhesion molecule-1, thereby inhibiting T lymphocyte extrava- inflammation (3), which exacerbates kidney function. Therefore, sation. The S1P receptor and PEPITEM are being investigated controlling the migration of T lymphocytes may serve as a ther- for development of novel therapeutic approaches for autoim- apeutic approach for SLE (4–6). mune diseases. Fingolimod (FTY720), a drug targeting the S1P Peptide inhibitor of transendothelial migration (PEPITEM) is an receptor, has been used for the treatment of multiple sclerosis endogenous peptide that promotes the synthesis of sphingosine 1 (14, 15), whereas PEPITEM is currently being investigated for the treatment of rheumatoid arthritis. *Department of Nephrology and Endocrinology, National Defense Medical College, However, the precise role of PEPITEM in the inflammatory Tokorozawa, Saitama 359-8513, Japan; †Department of Applied Biochemistry, Tokai pathology of SLE remains unclear, and the use of PEPITEM for University, Hiratsuka, Kanagawa 259-1207, Japan; ‡Department of Biochemistry, x SLE treatment has not yet been reported. Therefore, in this study, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan; and De- partment of Preventive Medicine and Public Health, National Defense Medical Col- we investigated whether exogenously administered PEPITEM can lege, Tokorozawa, Saitama 359-8513, Japan suppress lymphocyte infiltration into various organs of MRL/lpr ORCIDs: 0000-0001-9517-7746 (H.M.); 0000-0002-3496-1198 (M.A.); 0000-0003- mice. We also performed histological and biochemical analyses to 2892-1859 (M.T.). determine whether suppressing lymphocyte infiltration can pre- Received for publication February 25, 2019. Accepted for publication January 26, vent the development of nephritis. 2020. Address correspondence and reprint requests to Dr. Hidehito Matsubara, Department Materials and Methods of Nephrology and Endocrinology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail address: [email protected] Reagents Abbreviations used in this article: A/G, albumin/globulin; CDH, cadherin; DAB, The peptide and Abs used in this study are listed in Table I. 3,39-diaminobenzidine tetrahydrochloride; DN, double-negative; DPPC, dipalmitoyl- phosphatidylcholine; PEPITEM, peptide inhibitor of the transendothelial migration; Animals PTC, peritubular capillary; SLE, systemic lupus erythematosus; a-SMA, a–smooth muscle actin; S1P, sphingosine 1 phosphate; WT, Wilms tumor. Animal breeding and experimental procedures were performed in accor- dance with the animal experiment ethical guidelines of the National Defense Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 Medical College. Female MRL/lpr mice (18 wk old; SLC, Tokyo, Japan) www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900213 2 PEPITEM/CADHERIN 15 AXIS INHIBITS GLOMERULONEPHRITIS IN SLE were s.c. injected twice weekly with PEPITEM contained in dipalmi- and blood urea nitrogen (enzymatic method) levels and albumin/globulin toylphosphatidylcholine (DPPC) liposomes at 400 mg/dose (n = 12), as (A/G) ratio were measured (Oriental Yeast, Tokyo, Japan). Anti- previously described (16–18). Mice in the vehicle control group were dsDNA Ab was measured by REVIS anti-dsDNA Mouse ELISA Kit injected with only DPPC liposomes (n = 12). At 22 wk of age, mice (Shibayagi). were deeply anesthetized and euthanized, and blood was collected by cardiac puncture. The kidneys, spleen, and axillary lymph nodes were Immunohistochemistry and immunofluorescence analysis removed for histological and biochemical analyses. PEPITEM (amino acid sequence SVTEQGAELSNEER) was purified by postsynthesis Paraffin-embedded sections were stained with H&E and periodic acid– HPLC (SCRUM, Tokyo, Japan). The peptide (purity $95%) was dis- Schiff. The sections were heat-treated with citrate or Tris-EDTA buffer and solved in PBS and combined with DPPC liposomes prior to injection. then reacted with the primary Ab followed by the appropriate secondary Liposomes were readily accumulated in the reticuloendothelial system Ab. Immunoreactivity was visualized with 3,39-diaminobenzidine tetra- (kidney, spleen, etc.) (19), and were therefore used as a drug delivery hydrochloride (DAB) or by fluorescence detection. Frozen-fresh kidney system to target reactive peptides with a short half-life to the kidney. sections were also labeled with the primary Ab and corresponding sec- DPPC liposome was provided by Dr. Shimizu (Tokai University, Kanagawa, ondary Ab and were reacted with DAB. For detection of FITC-labeled Japan). PEPITEM (0.02 mg/ml), the sections were washed lightly and refixed with 4% paraformaldehyde at room temperature for 10 min. Thereafter, Lymphocyte analysis HRP-conjugated anti-FITC Ab (HPI, Burlington, MA) and anti-rabbit IgG-HRP (Nichirei, Tokyo, Japan) were allowed to react and then de- The excised kidney was sliced with a scalpel blade, passed through
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