The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice

Tang, Wei; Lü, Yi; Tian, Qingyun; Zhang, Yan; Guo, Fengjin; Liu, Guangyi; Syed, Nabeel Muzaffar; Lai, Yongjie; Lin, Edward; Kong, Li; Su, Jeffrey; Yin, Fang‐Fang; Ding, Aihao; Zanin-Zhorov, Alexandra; Dustin, Michael L.; Tao, Jing; Craft, Joseph; Yin, Zhinan; Feng, Jian Q.; Abramson, Steven B.; Yu, Xiuping; Liu, Chuanju

doi:10.1126/science.1199214

Cited by 677 publications

(1,037 citation statements)

References 36 publications

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“…In contrast to TNFa, Atsttrin exhibited a higher binding affinity for TNFR2, but a lower affinity for TNFR1. 29 In addition, it was also observed that TNF family ligands bind to the extracellular regions of TNFR1 and TNFR2 in which each receptor subunit contacts 2 adjacent ligand subunits typically via CRD2 and CRD3(cysteine-rich repeat domains, CRDs). 51,60 Deletion mutants of TNFR1 and TNFR2 used to map the binding of PGRN revealed that CRD2 and CRD3 of TNFR are essential for the interaction with PGRN, similar to the binding to TNFa.…”

Section: Discussionmentioning

confidence: 99%

“…51 Recently, it has been shown that PGRN binds to TNFR, interfering with the interaction between TNFa and TNFR. 29 However, the possibility that TNFR could be a specific receptor for PGRN-mediated effects in insulin resistance has never been tested, and it is still hard to clearly define the early stages of PGRN-mediated signaling from the plasma membrane. TNFR1 and TNFR2 do not share homology in the cytoplasmic domains but exhibit a low degree of similarity, which suggests that they are capable of inducing distinct cellular responses.…”

Section: Discussionmentioning

confidence: 99%

“…29 To clarify whether the effects of PGRN on ER stress and insulin resistance was dependent on TNFR pathway, we first verified that mRNA encoding both receptors was present and upregulated by PGRN exposure in hepatocytes and 3T3-L1 adipocytes ( Fig. 8A-B).…”

Section: Knockdown Of the Perk Pathway Blocks Insulin Resistance Indumentioning

confidence: 99%

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Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Zhou

Liu

et al. 2015

Cell Cycle

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Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the direct effects of PGRN in vivo and the underlying mechanisms between PGRN and impaired insulin sensitivity are not fully understood. In this study, mice treated with PGRN for 21 d exhibited the impaired glucose tolerance and insulin sensitivity, remarkable ER stress as well as attenuated insulin signaling in liver and adipose tissue but not in skeletal muscle. Furthermore, treatment of mice with phenyl butyric acid (PBA), a chemical chaperone alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling induced by PGRN. Consistent with these findings in vivo, we also observed that PGRN treatment induced ER stress, impaired insulin signaling in cultured hepatocytes and adipocytes, with such effects being partially nullified by blockade of PERK. Whereas PGRN-deficient hepatocytes and adipocytes were more refractory to palmitate-induced insulin resistance, indicating the causative role of the PERK-eIF2a axis of the ER stress response in action of PGRN. Collectively, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing ER stress via the PERK-eIF2a dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Zhou

Liu

et al. 2015

Cell Cycle

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“…Progranulin is a 593 amino acid glycoprotein consisting of 7.5 tandem repeats of a 12-cysteine granulin motif. Although its function is only incompletely understood, progranulin may be a physiological antagonist of tumor necrosis a signaling (Tang et al 2011). It has been reported to act on nerve cells by binding to sortilin following release from activated microglial cells (Hu et al 2010).…”

Section: Mutations In Grnmentioning

confidence: 99%

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Goedert¹,

Ghetti²,

Spillantini³

2011

Cold Spring Harbor Perspectives in Medicine

138

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“…Progranulin deficiency in mice leads to elevated neuro-inflammation, frontotemporal dementia [24][25][26], resulting in inflammation and progression of collagen-induced arthritis [27][28]. Progranulin has been also found in human blood and urine [28][29][30][31][32][33]. It has been recently used as a chronic inflamemation marker in obesity and type 2 diabetes mellitus [34].…”

Section: Introductionmentioning

confidence: 99%

Serum Progranulin Levels in Type 2 Diabetic Patients with Metabolic Syndrome

Shafaei

Marjani

Khoshnia

2016

Romanian Journal of Internal Medicine

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Introduction. The role of progranulin in individuals with metabolic syndrome is not exactly clear.We aimed to assess the serum level of progranulin in type 2 diabetic patients with and without metabolic syndrome and compare them with healthy controls.Methods. The study included 60 patients with type 2 diabetes and 30 healthy individuals as control groups. Biochemical parameters and progranulin levels were determined.Results. Subjects with metabolic syndrome showed significantly higher levels of triglyceride, waist circumference, BMI, systolic and diastolic blood pressure than subjects without metabolic syndrome and the control groups, while HDL-cholesterol level was significantly lower in subjects with metabolic syndrome. Fasting blood sugar was significantly higher in type 2 diabetic patients than in the control groups. Serum level of progranulin was slightly increased in subjects with metabolic syndrome. Serum progranulin level had no significant relationship with metabolic syndrome components.Conclusions. Serum progranulin was also not dependent on cardiometabolic risk factors for subjects with metabolic syndrome, but it could be considered for the management of type 2 diabetes mellitus. Further studies are recommended to explain the effect of progranulin on the pathogenesis of metabolic risk factors.

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The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice

Cited by 677 publications

References 36 publications

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2α-dependent manner

Frontotemporal Dementia: Implications for Understanding Alzheimer Disease

Serum Progranulin Levels in Type 2 Diabetic Patients with Metabolic Syndrome

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