Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-a Signaling Pathway

Ding, Fei1; Luo, Xi1; Tu, Yiting2; Duan, Xianlan1; Liu, Jia3; Jia, Lijing1; Zheng, Peilin1

2021-09-21

10.3389/fimmu.2021.705751

Frontiers in Immunology   影响因子和分区

1664-3224

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-beta-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-alpha and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-kappa B signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-alpha and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-alpha signaling pathway, which may provide novel insight into beta cell failure and T1D development.

Alpk1 pancreatic beta cells apoptosis pro-inflammatory cytokines TNF-alpha signaling

SCI

英语

第一 ; 通讯

Natural science foundation of Hunan province[2019JJ30036] ; Natural science foundation of Guangdong province[2020A1515010085] ; Shenzhen Municipal Science and Technology Innovation Committee Project[JCYJ20190807150619047]

Immunology

Immunology

WOS:000703526800001

FRONTIERS MEDIA SA

Web of Science

1.Southern Univ Sci & Technol, Jinan Univ, Affiliated Hosp 1, Clin Med Coll 2,Dept Endocrinol,Shenzhen Peoples, Shenzhen, Peoples R China
2.Fourth Peoples Hosp Shenzhen, Shenzhen Samii Int Med Ctr, Dept Neurol, Shenzhen, Peoples R China
3.Southern Univ Sci & Technol, Sch Med, Shenzhen, Peoples R China

Ding, Fei,Luo, Xi,Tu, Yiting,et al. Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-a Signaling Pathway[J]. Frontiers in Immunology,2021,12.

Ding, Fei.,Luo, Xi.,Tu, Yiting.,Duan, Xianlan.,Liu, Jia.,...&Zheng, Peilin.(2021).Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-a Signaling Pathway.Frontiers in Immunology,12.

Ding, Fei,et al."Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-a Signaling Pathway".Frontiers in Immunology 12(2021).