Legumain Regulates Regulatory T Cells in Hypertension.
Legumain Regulates Regulatory T Cells in Hypertension.
复制标题
DOI：
10.1161/circresaha.123.324010
复制
发表时间：
2024-01
影响因子：
20.1
通讯作者：
Matthew R Alexander;D.G. Harrison
中科院分区：
文献类型：
--
作者：
Matthew R Alexander;D.G. Harrison
CD 4+（分化簇4+）辅助性T细胞中的LGMN（legumain），特别是调节性T细胞（Tcells），在高血压发病机制中。LGMN，也称为天冬酰胺酰内肽酶，是一种内体和溶酶体半胱氨酸蛋白酶，其切割蛋白质如基质金属蛋白酶、组织蛋白酶和纤连蛋白的天冬酰胺残基。2 He等证明高血压小鼠和未经治疗的高血压患者的CD 4 + T细胞中LGMN水平升高。为了测试LGMN的因果作用，作者在小鼠的CD 4 + T细胞中遗传删除了LGMN，导致血压（BP）升高降低，血管紧张素II输注引起主动脉和肾纤维化。使用RR-11 a化合物对LGMN的全身药理学抑制作用概括了这些发现。然后，作者在患有CD 4 + T细胞LGMN缺陷的小鼠中耗尽Tlymphocyte。这消除了这些小鼠中的钝性高血压反应，表明LGMN在THP中的关键作用。为了进一步测试LGMN在TCLN中的作用，作者产生了特异性TCLN中LGMN缺乏的小鼠。LGMN缺陷型TCL 4在体外表现出更强的免疫抑制功能和更高水平的调节Treg分化和维持FOXP 3（叉头盒蛋白3）的介质。在体内，Treg LGMN缺陷小鼠在血管紧张素II输注后表现出降低的血压和终末器官损伤以及减少的炎性细胞因子产生。这些发现与LGMN在限制Treg免疫抑制功能和高血压发展中的作用一致。
LGMN (legumain) in CD4+(Cluster of Differentiation 4+) helper T cells, and specifically regulatory T cells (Tregs), in the pathogenesis of hypertension. LGMN, also known as asparaginyl endopeptidase, is an endosomal and lysosomal cysteine protease that cleaves asparagine residues of proteins such as matrix metalloproteinases, cathepsins, and fibronectin. 2 He et al demonstrate increased LGMN levels in CD4+ T cells of hypertensive mice and humans with untreated hypertension. To test causal roles for LGMN, the authors genetically deleted LGMN in CD4+ T cells of mice, resulting in reduced blood pressure (BP) elevations and aortic and renal fibrosis in response to angiotensin II infusion. These findings were recapitulated with systemic pharmacological inhibition of LGMN using the RR-11a compound. The authors then depleted Tregs in mice with CD4+ T cell LGMN deficiency. This abrogated the blunted hypertensive responses in these mice, suggesting a key role for LGMN in Tregs. To further test the role of LGMN in Tregs, the authors generated mice with LGMN deficiency specifically in Tregs. LGMN-deficient Tregs exhibited greater immunosuppressive function and higher levels of the mediator of Treg differentiation and maintenance FOXP3 (forkhead box protein 3) in vitro. In vivo, Treg LGMN–deficient mice exhibited reduced BP and end-organ damage and decreased inflammatory cytokine production after angiotensin II infusion. These findings are consistent with the role of LGMN in limiting Treg immunosuppressive function and hypertension development.