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

Physiological function of nerve injury-induced protein 1 and its role in relevant diseases

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。

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.