TNF receptor 2 pathway: drug target for autoimmune diseases

Faustman, Denise L.; Davis, Miriam

doi:10.1038/nrd3030

Cited by 372 publications

(365 citation statements)

References 138 publications

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“…Recently, it has been shown that PGRN binds to TNFR, interfering with the interaction between TNFA and TNFR (Tang et al 2011). When compared with TNFA?PGRN exhibited a higher affinity to both TNFR1 and TNFR2, and PGRN has approximately 600-fold higher binding affinity than TNFA (Bluml et al 2010, Faustman & Davis 2010. Similar to PGRN, Atsttrin, an engineered protein made of three PGRN fragments, inhibited the interaction between TNF and TNFR and, in turn, the downstream events of TNF/TNFR signaling.…”

Section: Discussionmentioning

confidence: 99%

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

Zhou¹,

Li²,

Liu³

et al. 2015

Journal of Molecular Endocrinology

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Progranulin (PGRN) has recently emerged as an important regulator for insulin resistance. However, the direct effect of PGRN in vivo and the underlying role of progranulin in adipose insulin resistance involving the autophagy mechanism is not fully understood. In this study, mice treated with PGRN for 21 days exhibited the impaired glucose tolerance and insulin sensitivity, remarkable adipose autophagy as well as attenuated insulin signaling via inhibition of mammalian target of rapamycin (mTOR) pathway. Furthermore, blockade of tumor necrosis factor receptor 1 (TNFR1) by TNFR1BP-Fc injection resulted in the restoration of impaired insulin sensitivity and insulin signaling induced by PGRN. Consistent with these findings in vivo, PGRN treatment induced defective insulin signaling, abnormal autophagic and mitochondrial activity in cultured adipocytes, while such effects were nullified by the blockade of TNFR1. In addition, PGRN-deficient adipocytes were more refractory to tunicamycin-or dexamethasone-induced insulin resistance, indicating the causative role of the TNFR1 pathway in the action of PGRN. Collectively, our findings support the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing autophagy via the TNFR1-dependent mechanism.

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Section: Discussionmentioning

confidence: 99%

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

Zhou¹,

Li²,

Liu³

et al. 2015

Journal of Molecular Endocrinology

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show abstract

“…38,[57][58][59] Similar to PGRN, Atsttrin, an engineered protein made of 3 PGRN fragments, inhibited the interaction between TNF and TNFR, and in turn, the downstream events of TNF/TNFR signaling. In contrast to TNFa, Atsttrin exhibited a higher binding affinity for TNFR2, but a lower affinity for TNFR1.…”

Section: Discussionmentioning

confidence: 99%

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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“…TNFα leading immune defenses are aimed at protecting a localized area from invasion or injury but they may be also involved in controlling whether target cells die or live (i.e., apoptosis or cell survival and proliferation). Thus, defective immune cells in autoimmune diseases may provoke destruction of cells and tissues being coordinated by anomalous TNFα activity and/or response (27).…”

Section: Regulation and Dysregulation Of Tnfr1mentioning

confidence: 99%

Inflammation in the spotlight—clinical relevance of genetic variants affecting nuclear factor κB and tumor necrosis factor receptor 1

Ortega

Fernández‐Real

2017

Ann. Transl. Med.

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TNF receptor 2 pathway: drug target for autoimmune diseases

Cited by 372 publications

References 138 publications

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

Progranulin induces adipose insulin resistance and autophagic imbalance via TNFR1 in mice

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

Inflammation in the spotlight—clinical relevance of genetic variants affecting nuclear factor κB and tumor necrosis factor receptor 1

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