Key Points The PEPITEM/CDH15 axis is involved in homeostasis in pathological inflammation. PEPITEM could be used as a therapeutic agent for systemic lupus erythematosus. 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 transendothelial 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/lpr mice and whether lymphocyte infiltration is suppressed by exogenously 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 deposition, 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, thereby preserving the kidney structure and reducing proteinuria. Thus, PEPITEM administration may be considered as a potential therapeutic tool for systemic lupus erythematosus.

中文翻译：

---

PEPITEM/钙粘蛋白 15 轴抑制系统性红斑狼疮小鼠模型中的 T 淋巴细胞浸润和肾小球肾炎

要点 PEPITEM/CDH15 轴参与病理性炎症的稳态。PEPITEM 可用作系统性红斑狼疮的治疗剂。考虑到 1 磷酸鞘氨醇对淋巴细胞迁移的控制与炎症相关病理有关，因此控制肾脏淋巴细胞浸润是狼疮性肾炎的潜在治疗策略。最近报道了跨内皮迁移 (PEPITEM)/钙粘蛋白 (CDH) 15 轴的肽抑制剂可促进 1 磷酸鞘氨醇分泌。在这项研究中，我们调查了 CDH15 是否在 MRL/lpr 小鼠的肾脏中表达，以及淋巴细胞浸润是否被外源性给药的 PEPITEM 抑制。将小鼠（18 周龄）随机分为 4 周治疗组，这些治疗组接受包裹在二棕榈酰磷脂酰胆碱脂质体中的 PEPITEM 或 PBS。PEPITEM 治疗抑制了肾脏、脾脏和腋窝淋巴结的增大，这也阻止了双阴性 T 淋巴细胞浸润肾脏和肾小球 IgG/C3 沉积、减少蛋白尿和增加足细胞密度。免疫组织化学分析显示，PEPITEM 受体 CDH15 在 22 周龄的狼疮小鼠的肾小球和肾小动脉、皮肤和腹膜的血管内皮细胞上表达，但在 4 周龄的小鼠中不表达。这些结果表明 PEPITEM 抑制淋巴细胞迁移和浸润到肾脏中，从而保护肾脏结构并减少蛋白尿。因此，