Nonenzymatic function of DPP4 promotes diabetes-associated cognitive dysfunction through IGF-2R/PKA/SP1/ERp29/IP3R2 pathway-mediated impairment of Treg function and M1 microglia polarization

被引：21

作者：

Hui, Ya ^{[1
,2
]}

Xu, Zhiqiang ^{[1
,2
]}

Li, Jiaxiu ^{[1
,2
,3
]}

Kuang, Liuyu ^{[1
]}

Zhong, Yuanmei ^{[1
]}

Tang, Yunyun ^{[1
]}

Wei, Junjie ^{[4
]}

Zhou, Huimin ^{[5
]}

Zheng, Tianpeng ^{[1
,2
,3
,6
]}

机构：

[1] Guilin Med Univ, Affiliated Hosp 2, Dept Endocrinol & Metab, Guilin 541199, Guangxi, Peoples R China

[2] Guilin Med Univ, Guangxi Key Lab Diabetic Syst Med, Guilin 541199, Guangxi, Peoples R China

[3] Guilin Med Univ, Guangxi Key Lab Brain & Cognit Neurosci, Guilin 541199, Guangxi, Peoples R China

[4] Guilin Med Univ, Lingui Clin Med Coll, Guilin 541199, Guangxi, Peoples R China

[5] Guilin Med Univ, Dept Gen Med, Guilin 541199, Guangxi, Peoples R China

[6] Guilin Med Univ, Affiliated Hosp 2, Guangxi Hlth Commiss Key Lab Glucose & Lipid Metab, Guilin 541199, Guangxi, Peoples R China

来源：

METABOLISM-CLINICAL AND EXPERIMENTAL | 2023年 / 138卷

基金：

中国国家自然科学基金;

关键词：

Dipeptidyl peptidase-4; Regulatory T cells; Mitochondria calcium overload; Microglia; Cognitive impairment; Type; 2; diabetes; CELL; MITOCHONDRIA; PROGRESSION; DISEASE; TARGET; ERP29;

D O I：

10.1016/j.metabol.2022.155340

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Impairment of regulatory T (Treg) cells function is implicated in the pathogenesis of immune imbalance-mediated cognitive impairment. A complete understanding of whether and how this imbalance affect cognitive function in type 2 diabetes is lacking, and the driver affecting this imbalance remains unknown. Methods: We examined the impact of enzymatic and non-enzymatic function of DPP4 on Treg cell impairment, microglia polarization and diabetes-associated cognitive defects and identified its underlying mechanism in type 2 diabetic patients with cognitive impairment and in db/db mice. Results: We report that DPP4 binds to IGF2-R on Treg cell surface and activates PKA/SP1 signaling, which upregulate ERp29 expression and promote its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting mitochondria-associated ER membrane formation and mitochondria calcium overload in Tregs. This, in turn, impairs Tregs function and polarizes microglia toward a pro-inflammatory phenotype in the hippocampus and finally leads to neuroinflammation and cognitive impairment in type 2 diabetes. Importantly, inhibiting DPP4 enzymatic activity in type 2 diabetic patients or mutating DPP4 enzymatic active site in db/db mice did not reverse these changes. However, IGF-2R knockdown or blockade ameliorated these effects both in vivo and in vitro. Conclusion: These findings highlight the nonenzymatic role of DPP4 in impairing Tregs function, which may facilitate the design of novel immunotherapies for diabetes-associated cognitive impairment.

引用

页数：18