Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

Yang, Junling; Kou, Jinghong; Lim, Jinhyuk; Lalonde, Robert; Fukuchi, Ken Ichiro

doi:10.1016/j.bbi.2015.11.005

Cited by 6 publications

(8 citation statements)

References 101 publications

(115 reference statements)

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“…The bioactivity of IL-17A produced by the AAV-IL-17A vector was confirmed using 3T3 cells described previously (Yang et al , 2016). To explore the potential role of IL-17A in AD, we intracranially delivered rAAV5-IL-17A into 2-month-old TgAPPswe/PS1dE9 mice.…”

Section: Resultsmentioning

confidence: 93%

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Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Yang

Kou

Lalonde

et al. 2017

Brain, Behavior, and Immunity

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Neuroinflammation is a pervasive feature of Alzheimer’s disease (AD) and characterized by activated microglia, increased proinflammatory cytokines and/or infiltrating immune cells. T helper 17 (Th17) cells are found in AD brain parenchyma and interleukin-17A (IL-17A) is identified around deposits of aggregated amyloid β protein (Aβ). However, the role of IL-17A in AD pathogenesis remains elusive. We overexpressed IL-17A in an AD mouse model via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated intracranial gene delivery. AD model mice subjected to injection of a vehicle (PBS) or rAAV5 carrying the lacZ gene served as controls. IL-17A did not exacerbate neuroinflammation in IL-17A-overexpressing mice. We found that IL-17A overexpression markedly improved glucose metabolism, decreased soluble Aβ levels in the hippocampus and cerebrospinal fluid, drastically reduced cerebral amyloid angiopathy, and modestly but significantly improved anxiety and learning deficits. Moreover, the ATP-binding cassette subfamily A member 1 (ABCA1), which can transport Aβ from the brain into the blood circulation, significantly increased in IL-17A-overexpressing mice. In vitro treatment of brain endothelial bEnd.3 cells with IL-17A induced a dose-dependent increase in protein expression of ABCA1 through ERK activation. Our study suggests that IL-17A may decrease Aβ levels in the brain by upregulating ABCA1 in blood-brain barrier endothelial cells.

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Section: Resultsmentioning

confidence: 93%

“…A rAAV vector, rAAV5-IL-17A, was prepared as described previously (Yang et al , 2016). A control rAAV vector encoding LacZ, rAAV5-LacZ, was similarly prepared.…”

Section: Methodsmentioning

confidence: 99%

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Yang

Kou

Lalonde

et al. 2017

Brain, Behavior, and Immunity

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“…The present results suggested the presence of an indirect mechanism during the expression of rate-limiting enzymes mediated by miR-218. Previous studies have indicated that Akt, JNK, ERK and NF-κB signaling pathways play important roles in glucose metabolism regulation (33)(34)(35)(36)(37)(38)(39)(40). Therefore, in the present study the phosphorylation of these proteins was detected in A549-GLUT1 cells after transfection with miR-218 mimics.…”

Section: Discussionmentioning

confidence: 67%

miR‑218 inhibits glucose metabolism in non‑small cell lung cancer via the NF‑κB signaling pathway

et al. 2020

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High glucose metabolism is recognized as one of the hallmarks of cancer and increased expression levels of several key factors involved in glucose metabolism have been reported in non-small cell lung cancer (NSCLC). Previous studies showed that microRNA (miR)-218 is reduced in NSCLC, but its function in glucose metabolism in NSCLC is not fully understood. The present study aimed to investigate the effect of miR-218 on glucose metabolism in NSCLC cell lines and the underlying molecular mechanism. The present results suggested that miR-218 reduced glucose consumption, the mechanism of glycolysis and activity in the pentose phosphate pathway. In addition, glucose transporter 1 (GLUT1) was identified to be a direct target of miR-218, while overexpression of GLUT1 did not abolish the effect of miR-218 on glucose metabolism. The present results indicated that phosphorylation of NF-κB p65 was significantly decreased by miR-218 in NSCLC cells and that activation of NF-κB led to the inhibition of miR-218 regulation of glucose metabolism. In conclusion, the present results suggested that miR-218 downregulated glucose metabolism in NSCLC not only by directly targeting GLUT1, but also via the NF-κB signaling pathway.

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“…At the age of 11.5 months, the mice were conducted for the IPGTT and ITT, as previously described [ 30 , 31 ]. The animals ( n = 12/group) were fasted for 16 h, weighed, and intraperitoneally injected with D-glucose (1.5 g/kg) for the IPGTT.…”

Section: Methodsmentioning

confidence: 99%

“…Epididymal adipocytes were prepared as previously described [ 31 , 32 ]. In brief, adipose tissue ( n = 4/group) was digested at 37°C in PBS (without calcium and magnesium) containing 2% bovine serum albumin (BSA) and 2 mg/ml collagenase VI (Sigma, St. Louis, MO) for 45 min.…”

Section: Methodsmentioning

confidence: 99%

TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Is Involved in Glucose Metabolism in Adipose Tissue through the Insulin/AKT Signaling Pathway

Yang

Fukuchi

2020

International Journal of Endocrinology

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Obesity significantly increases the risk of developing type 2 diabetes mellitus and other metabolic diseases. Obesity is associated with chronic low-grade inflammation in white adipose tissues, which is thought to play an essential role in developing insulin resistance. Many lines of evidence indicate that toll-like receptors (TLRs) and their downstream signaling pathways are involved in development of chronic low-grade inflammation and insulin resistance, which are associated with obesity. Mice lacking molecules positively involved in the TLR signaling pathways are generally protected from high-fat diet-induced inflammation and insulin resistance. In this study, we have determined the effects of genetic deficiency of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) on food intake, bodyweight, glucose metabolism, adipose tissue macrophage polarization, and insulin signaling in normal chow diet-fed mice to investigate the role of the TRIF-dependent TLR signaling in adipose tissue metabolism and inflammation. TRIF deficiency (TRIF−/−) increased food intake and bodyweight. The significant increase in bodyweight in TRIF−/− mice was discernible as early as 24 weeks of age and sustained thereafter. TRIF−/− mice showed impaired glucose tolerance in glucose tolerance tests, but their insulin tolerance tests were similar to those in TRIF+/+ mice. Although no difference was found in the epididymal adipose mass between the two groups, the percentage of CD206+ M2 macrophages in epididymal adipose tissue decreased in TRIF−/− mice compared with those in TRIF+/+ mice. Furthermore, activation of epididymal adipose AKT in response to insulin stimulation was remarkably diminished in TRIF−/− mice compared with TRIF+/+ mice. Our results indicate that the TRIF-dependent TLR signaling contributes to maintaining insulin/AKT signaling and M2 macrophages in epididymal adipose tissue under a normal chow diet and provide new evidence that TLR4-targeted therapies for type 2 diabetes require caution.

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Intracranial delivery of interleukin-17A via adeno-associated virus fails to induce physical and learning disabilities and neuroinflammation in mice but improves glucose metabolism through AKT signaling pathway

Cited by 6 publications

References 101 publications

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer’s disease

miR‑218 inhibits glucose metabolism in non‑small cell lung cancer via the NF‑κB signaling pathway

TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Is Involved in Glucose Metabolism in Adipose Tissue through the Insulin/AKT Signaling Pathway

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