神经损伤诱导蛋白1的生理功能及其在相关疾病中的作用

doi:10.3969/j.issn.1674-8115.2023.03.012

摘要/Abstract

摘要：

神经损伤诱导蛋白1（nerve injury-induced protein 1，NINJ1）是一种位于细胞表面的黏附分子，包含1个胞外黏附结构域和2个跨膜结构域。NINJ1因最初在受损神经末梢中被发现而得名，其在多种组织和细胞中均有表达，在上皮细胞和髓系细胞中高表达。NINJ1能够促进受损神经纤维中施万细胞前体和多能性周细胞向施万细胞定向分化，从而调节神经修复和髓鞘再生。在糖尿病引发的周围神经及血管损伤中，NINJ1不仅能够促进神经损伤恢复，还能通过血管生成素1（angiopoietin 1，ANG1）/酪氨酸激酶受体tie-2（tyrosine-protein kinase receptor tie-2，TIE2）信号通路调控海绵体血管新生。NINJ1还参与调控玻璃体血管网成熟，这与周细胞ANG1以及血管生成素2（angiopoietin 2，ANG2）比例变化相关。NINJ1主要通过胞外黏附结构域介导髓系细胞跨内皮迁移，从而加重中枢神经系统炎症；但其经基质金属蛋白酶9（matrix metalloproteinase 9，MMP9）剪切后的片段能够抑制巨噬细胞炎性活化，其模拟肽有望用于治疗动脉粥样硬化。除调控细胞炎性表型外，NINJ1主动介导质膜破裂，调控炎症细胞程序性死亡，进而参与宿主抵御外源性感染过程。此外，NINJ1在多种肿瘤组织中表达上调，其与抑癌蛋白P53形成相互调控的闭环，介导肿瘤的生长及转移。该文总结了NINJ1的生理功能及其在多种病理过程中发挥的关键调控作用，并探讨了其在免疫调节和组织再生中的潜在价值，以期为损伤、炎症、肿瘤相关疾病的防治提供新思路。

关键词: 神经损伤诱导蛋白1, 神经损伤, 肿瘤, 血管新生, 炎症

Abstract:

Nerve injury-induced protein 1 (NINJ1) is a cell-surface adhesion molecule containing an extracellular adhesion domain and two transmembrane domains. NINJ1 is named for its original discovery in damaged nerve endings. It is expressed in a variety of tissues and cells, with high expression in epithelial and myeloid cells. NINJ1 regulates nerve regeneration by promoting Schwann cell precursors and pluripotent pericytes to differentiate into Schwann cells. In diabetes-induced peripheral nerve and vascular damage, NINJ1 not only promotes nerve repair, but also regulates penile angiogenesis via angiopoietin 1 (ANG1)/tyrosine-protein kinase receptor tie-2 (TIE2) signaling pathway. NINJ1 also participates in the maturation of vitreous vascular network, which is associated with changes in the proportion of ANG1 and ANG2 in pericytes. NINJ1 mediates inflammatory cell migration across the endothelium through its extracellular adhesion domain, and thus aggravates central nervous system inflammation. However, NINJ1 cleaved by matrix metalloproteinase 9 (MMP9) can inhibit macrophage inflammatory activation, and its mimic peptide is expected to treat atherosclerosis. In addition to regulating the inflammatory phenotypes of myeloid cells, NINJ1 actively mediates plasma membrane rupture and regulates programmed cell death, which is involved in host defense against exogenous infection. Moreover, NINJ1 is up-regulated in a variety of tumor tissues, and regulates tumor suppressor P53 activity via the P53-NINJ1 loop, which mediates tumor growth and metastasis. The current review summarizes the physiological function of NINJ1 and its key regulatory roles in pathological processes, and discusses its potential value in immunomodulation and tissue regeneration, in order to provide new ideas for the prevention and treatment of injury, inflammation and tumor-related diseases.

Key words: nerve injury-induced protein 1 (NINJ1), nerve injury, tumor, angiogenesis, inflammation

中图分类号:

吴昭瑜, 许之珏, 蒲蕻吉, 王新, 陆信武. 神经损伤诱导蛋白1的生理功能及其在相关疾病中的作用[J]. 上海交通大学学报（医学版）, 2023, 43(3): 358-364.

WU Zhaoyu, XU Zhijue, PU Hongji, WANG Xin, LU Xinwu. Physiological function of nerve injury-induced protein 1 and its role in relevant diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(3): 358-364.

参考文献 46

1	ARAKI T, MILBRANDT J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth[J]. Neuron, 1996, 17(2): 353-361.
2	IGNATIUS M J, GEBICKE-HÄRTER P J, SKENE J H, et al. Expression of apolipoprotein E during nerve degeneration and regeneration[J]. Proc Natl Acad Sci USA, 1986, 83(4): 1125-1129.
3	FUJITA Y, KAWAMOTO A. Ninjurin1: a novel regulator of angiogenesis mediated by pericytes[J]. Circ J, 2015, 79(6): 1218-1219.
4	EKANAYAKE P, AHN M, KIM J, et al. Immunohistochemical localization of nerve injury-induced protein-1 in mouse tissues[J]. Anat Cell Biol, 2019, 52(4): 455-461.
5	LEE H J, AHN B J, SHIN M W, et al. Ninjurin1: a potential adhesion molecule and its role in inflammation and tissue remodeling[J]. Mol Cells, 2010, 29(3): 223-227.
6	AHN B J, LEE H J, SHIN M W, et al. Ninjurin1 is expressed in myeloid cells and mediates endothelium adhesion in the brains of EAE rats[J]. Biochem Biophys Res Commun, 2009, 387(2): 321-325.
7	AHN B J, LE H, SHIN M W, et al. Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice[J]. J Biol Chem, 2014, 289(6): 3328-3338.
8	IFERGAN I, KEBIR H, TEROUZ S, et al. Role of ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions[J]. Ann Neurol, 2011, 70(5): 751-763.
9	YIN G N, CHOI M J, KIM W J, et al. Inhibition of ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse[J]. Proc Natl Acad Sci USA, 2014, 111(26): E2731-E2740.
10	YIN G N, KIM W J, JIN H R, et al. Nerve injury-induced protein 1 (ninjurin-1) is a novel therapeutic target for cavernous nerve injury-induced erectile dysfunction in mice[J]. J Sex Med, 2013, 10(6): 1488-1501.
11	KIM D K, YIN G N, RYU J K, et al. Differential expression of nerve injury-induced protein 1 (ninjurin 1) in in vivo and in vitro models for diabetic erectile dysfunction[J]. Korean J Urol, 2012, 53(9): 636-642.
12	CHO S J, ROSSI A, JUNG Y S, et al. Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality[J]. Proc Natl Acad Sci USA, 2013, 110(23): 9362-9367.
13	YANG H J, ZHANG J, YAN W S, et al. Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner[J]. Proc Natl Acad Sci USA, 2017, 114(43): 11500-11505.
14	KAYAGAKI N, KORNFELD O S, LEE B L, et al. NINJ1 mediates plasma membrane rupture during lytic cell death[J]. Nature, 2021, 591(7848): 131-136.
15	TOMITA Y, HORIUCHI K, KANO K, et al. Ninjurin 1 mediates peripheral nerve regeneration through Schwann cell maturation of NG2-positive cells[J]. Biochem Biophys Res Commun, 2019, 519(3): 462-468.
16	KIM J W, MOON A R, KIM J H, et al. Up-Regulation of ninjurin expression in human hepatocellular carcinoma associated with cirrhosis and chronic viral hepatitis[J]. Mol Cells, 2001, 11(2): 151-157.
17	TOYAMA T, SASAKI Y, HORIMOTO M, et al. Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells[J]. J Hepatol, 2004, 41(4): 637-643.
18	JANG Y S, KANG J H, WOO J K, et al. Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway[J]. Int J Cancer, 2016, 139(2): 383-395.
19	HYUN S Y, MIN H Y, LEE H J, et al. Ninjurin1 drives lung tumor formation and progression by potentiating Wnt/β-catenin signaling through Frizzled2-LRP6 assembly[J]. J Exp Clin Cancer Res, 2022, 41(1): 133.
20	PARK J, JOUNG J Y, HWANG J E, et al. Ninjurin1 is up-regulated in circulating prostate tumor cells and plays a critical role in prostate cancer cell motility[J]. Anticancer Res, 2017, 37(4): 1687-1696.
21	KANG J H, WOO J K, JANG Y S, et al. Radiation potentiates monocyte infiltration into tumors by ninjurin1 expression in endothelial cells[J]. Cells, 2020, 9(5): 1086.
22	WOO J K, JANG Y S, KANG J H, et al. Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling[J]. Oncotarget, 2016, 7(20): 29592-29604.
23	MATSUKI M, KABARA M, SAITO Y, et al. Ninjurin1 is a novel factor to regulate angiogenesis through the function of pericytes[J]. Circ J, 2015, 79(6): 1363-1371.
24	MINOSHIMA A, KABARA M, MATSUKI M, et al. Pericyte-specific ninjurin1 deletion attenuates vessel maturation and blood flow recovery in hind limb ischemia[J]. Arterioscler Thromb Vasc Biol, 2018, 38(10): 2358-2370.
25	KIM S W, LEE H K, SEOL S I, et al. Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain[J]. Sci Rep, 2020, 10(1): 16656.
26	HORIUCHI K, KANO K, MINOSHIMA A, et al. Pericyte-specific deletion of ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature[J]. Am J Physiol Heart Circ Physiol, 2021, 320(6): H2438-H2447.
27	WANG X, QIN J B, ZHANG X, et al. Functional blocking of ninjurin1 as a strategy for protecting endothelial cells in diabetes mellitus[J]. Clin Sci (Lond), 2018, 132(2): 213-229.
28	LEE H K, LEE H, LUO L D, et al. Induction of nerve injury-induced protein 1 (ninjurin 1) in myeloid cells in rat brain after transient focal cerebral ischemia[J]. Exp Neurobiol, 2016, 25(2): 64-74.
29	LEE H K, KIM I D, LEE H, et al. Neuroprotective and anti-inflammatory effects of a dodecamer peptide harboring ninjurin 1 cell adhesion motif in the postischemic brain[J]. Mol Neurobiol, 2018, 55(7): 6094-6111.
30	JEON S, KIM T K, JEONG S J, et al. Anti-inflammatory actions of soluble ninjurin-1 ameliorate atherosclerosis[J]. Circulation, 2020, 142(18): 1736-1751.
31	HWANG S J, AHN B J, SHIN M W, et al. miR-125a-5p attenuates macrophage-mediated vascular dysfunction by targeting Ninjurin1[J]. Cell Death Differ, 2022, 29(6): 1199-1210.
32	JUNG H J, KANG J H, PAK S, et al. Detrimental role of nerve injury-induced protein 1 in myeloid cells under intestinal inflammatory conditions[J]. Int J Mol Sci, 2020, 21(2): 614.
33	CHOI H, BAE S J, CHOI G, et al. Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance[J]. FASEB J, 2020, 34(6): 8702-8720.
34	CHOI S, WOO J K, JANG Y S, et al. Ninjurin1 plays a crucial role in pulmonary fibrosis by promoting interaction between macrophages and alveolar epithelial cells[J]. Sci Rep, 2018, 8: 17542.
35	AHN B J, LE H, SHIN M W, et al. Ninjurin1 enhances the basal motility and transendothelial migration of immune cells by inducing protrusive membrane dynamics[J]. J Biol Chem, 2014, 289(32): 21926-21936.
36	JENNEWEIN C, SOWA R, FABER A C, et al. Contribution of ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation[J]. Am J Respir Cell Mol Biol, 2015, 53(5): 656-663.
37	SHIN M W, BAE S J, WEE H J, et al. Ninjurin1 regulates lipopolysaccharide-induced inflammation through direct binding[J]. Int J Oncol, 2016, 48(2): 821-828.
38	LEE H J, AHN B J, SHIN M W, et al. Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development[J]. Cell Death Differ, 2009, 16(10): 1395-1407.
39	KAYAGAKI N, DIXIT V M. Rescue from a fiery death: a therapeutic endeavor[J]. Science, 2019, 366(6466): 688-689.
40	GAIDT M M, HORNUNG V. Pore formation by GSDMD is the effector mechanism of pyroptosis[J]. EMBO J, 2016, 35(20): 2167-2169.
41	KRISTJANSSON R P, ODDSSON A, HELGASON H, et al. Common and rare variants associating with serum levels of creatine kinase and lactate dehydrogenase[J]. Nat Commun, 2016, 7: 10572.
42	NEWTON K, DIXIT V M, KAYAGAKI N. Dying cells fan the flames of inflammation[J]. Science, 2021, 374(6571): 1076-1080.
43	WANG Y P, SHAO F. NINJ1, rupturing swollen membranes for cataclysmic cell lysis[J]. Mol Cell, 2021, 81(7): 1370-1371.
44	PANDEY A, SHEN C, FENG S Y, et al. Cell biology of inflammasome activation[J]. Trends Cell Biol, 2021, 31(11): 924-939.
45	TAJOURI L, MELLICK A S, ASHTON K J, et al. Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis[J]. Brain Res Mol Brain Res, 2003, 119(2): 170-183.
46	MARES J, SZAKACSOVA M, SOUKUP V, et al. Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results[J]. Neoplasma, 2013, 60(3): 295-301.

[1]	吴兵, 李小敏, 柳思宇, 赵露露, 武文, 郝永强, 艾松涛. 改良3D打印病理切片盒在骨肿瘤病理拼接中的应用初探[J]. 上海交通大学学报（医学版）, 2023, 43(2): 180-187.
[2]	过丽强, 赵世天, 舒冰. Notch信号通路在骨折愈合过程中作用的研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(2): 222-229.
[3]	吴振恺, 邓博, 潘瑜, 丁峰. 酰基羧酸水解酶在疾病中的作用及机制研究进展[J]. 上海交通大学学报（医学版）, 2023, 43(1): 101-107.
[4]	谢小雷, 江佩欣, 张敬鸿, 莫骏健, 吴可凡, 曾康逸. 视网膜母细胞瘤结合锌指蛋白1调控肥胖和肿瘤信号通路研究综述[J]. 上海交通大学学报（医学版）, 2023, 43(1): 114-119.
[5]	杨玲, 侯黎莉, 赵燕, 陈卫宏, 张金凤, 毛艳. 口腔癌患者张口受限患病率的meta分析[J]. 上海交通大学学报（医学版）, 2023, 43(1): 61-69.
[6]	马芳芳, 秦洁洁, 任灵杰, 唐笑梅, 刘佳, 施敏敏, 蒋玲曦. 基于水凝胶微球建立胰腺癌原代细胞的3D培养模型[J]. 上海交通大学学报（医学版）, 2023, 43(1): 79-87.
[7]	杨文倩, 陈迟琪, 赵路, 曹力元, 夏一秋, 卢智刚, 郑俊克. 免疫抑制性受体LILRB2促进新型冠状病毒刺突蛋白介导的炎症过程[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1188-1196.
[8]	崔锡炜, 钟民衎, 热汗姑丽·艾买尔, 王智超, 李青峰. 人多效蛋白抑制恶性周围神经鞘瘤转移的机制研究[J]. 上海交通大学学报（医学版）, 2022, 42(9): 1225-1238.
[9]	褚云开, 廖春华, 邓华云, 黄雷. 黏蛋白1与肿瘤相关蛋白的调控网络研究[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1024-1033.
[10]	邱佳辉, 蔡谦谦, 杨彦, 程非池, 裘正军, 黄陈. 神经脉管浸润联合肿瘤间质比对结直肠癌预后的预测价值[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1070-1080.
[11]	林家俞, 秦洁洁, 蒋玲曦. 肿瘤微环境中免疫细胞的代谢研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1122-1130.
[12]	阿婷曦, 邵春益, 傅瑶. 调节性T细胞在眼表疾病中作用的研究进展[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1145-1150.
[13]	邢正文, 吴滢, 王雪莉, 王庆煜, 王文婷, 李治, 张彬, 金晶. 儿童CIC重排肉瘤的临床病理特征[J]. 上海交通大学学报（医学版）, 2022, 42(8): 1151-1157.
[14]	刘宏强, 陆艳青, 高宇轩, 王一云, 王传东, 张晓玲. 构建高效载体OPEI沉默TRAF6促进骨关节炎软骨再生的研究[J]. 上海交通大学学报（医学版）, 2022, 42(7): 846-857.
[15]	王雨心, 孙瑞琪, 刘坚华, 何伟娜. 开发用于肿瘤微环境成像的pH敏感荧光探针[J]. 上海交通大学学报（医学版）, 2022, 42(7): 875-884.