Angiogenic and Arthritogenic Properties of the Soluble Form of CD13
Angiogenic and Arthritogenic Properties of the Soluble Form of CD13
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DOI：
10.4049/jimmunol.1801276
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发表时间：
2019-07-15
影响因子：
4.4
通讯作者：
Amin, Mohammad A.
中科院分区：
文献类型：
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作者：
Du, Yuxuan;Lu, Chenyang;Amin, Mohammad A.
氨肽酶N/CD 13由成纤维细胞样滑膜细胞（FLS）和单核细胞（MN）在发炎的人滑膜组织（ST）中表达。本研究检测了可溶性CD 13（sCD 13）在血管生成、MN迁移、信号分子磷酸化和关节炎诱导中的作用。使用sCD 13和CD 13耗尽的类风湿性关节炎（RA）滑液（SF）检查sCD 13在血管生成和MN迁移中的作用。使用酶失活突变体CD 13和完整野生型（WT）CD 13来确定其酶活性是否有助于关节炎相关功能。通过Western印迹法测定CD 13诱导的信号分子磷酸化。评价sCD 13对RA ST和RA FLS细胞因子分泌的影响。将sCD 13注射到C57 BL/6小鼠膝关节中以评估其致关节炎性。sCD 13诱导血管生成，是MN和U937细胞的有效化学引诱物。Erk 1/2、Src、NF-κ B、Jnk抑制剂和百日咳毒素（一种G蛋白偶联受体抑制剂）可降低sCD 13刺激的趋化性。CD 13缺失的RA SF诱导的MN迁移明显少于假缺失的SF，并且向CD 13缺失的RA SF中添加突变体或WT CD 13同样恢复了MN迁移。sCD 13和重组WT或突变型CD 13对信号分子磷酸化具有相似的作用，表明CD 13的酶活性在这些功能中没有作用。CD 13增加RA FLS的促炎细胞因子的表达，并且CD 13中和Ab抑制RA ST器官培养物的细胞因子分泌。注射CD 13的小鼠膝关节表现出周长增加和促炎介质表达。这些数据支持sCD 13在RA和急性炎症性关节炎中起关键作用的概念。
Aminopeptidase N/CD13 is expressed by fibroblast-like synoviocytes (FLS) and monocytes (MNs) in inflamed human synovial tissue (ST). This study examined the role of soluble CD13 (sCD13) in angiogenesis, MN migration, phosphorylation of signaling molecules, and induction of arthritis. The contribution of sCD13 was examined in angiogenesis and MN migration using sCD13 and CD13-depleted rheumatoid arthritis (RA) synovial fluids (SFs). An enzymatically inactive mutant CD13 and intact wild-type (WT) CD13 were used to determine whether its enzymatic activity contributes to the arthritis-related functions. CD13-induced phosphorylation of signaling molecules was determined by Western blotting. The effect of sCD13 on cytokine secretion from RA ST and RA FLS was evaluated. sCD13 was injected into C57BL/6 mouse knees to assess its arthritogenicity. sCD13 induced angiogenesis and was a potent chemoattractant for MNs and U937 cells. Inhibitors of Erk1/2, Src, NF-kappa B, Jnk, and pertussis toxin, a G protein-coupled receptor inhibitor, decreased sCD13-stimulated chemotaxis. CD13-depleted RA SF induced significantly less MN migration than sham-depleted SF, and addition of mutant or WT CD13 to CD13-depleted RA SF equally restored MN migration. sCD13 and recombinant WT or mutant CD13 had similar effects on signaling molecule phosphorylation, indicating that the enzymatic activity of CD13 had no role in these functions. CD13 increased the expression of proinflammatory cytokines by RA FLS, and a CD13 neutralizing Ab inhibited cytokine secretion from RA ST organ culture. Mouse knee joints injected with CD13 exhibited increased circumference and proinflammatory mediator expression. These data support the concept that sCD13 plays a pivotal role in RA and acute inflammatory arthritis.