Tumor necrosis factor-α-stimulated brain pericytes possess a unique cytokine and chemokine release profile and enhance microglial activation

Matsumoto, Junichi; Takata, Fuyuko; Machida, Takashi; Takahashi, Hiroyuki; Soejima, Yuki; Funakoshi, Mikiko; Futagami, Koujiro; Yamauchi, Atsushi; Dohgu, Shinya; Kataoka, Yasufumi

doi:10.1016/j.neulet.2014.06.052

Cited by 73 publications

(64 citation statements)

References 28 publications

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“…Real-time quantitative PCR was carried out as previously described [41]. The specific primer-probe sets for rat IL-1β, IL-6, TNF-α and GAPDH were purchased from Takara (Shiga, Japan).…”

Section: Methodsmentioning

confidence: 99%

Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model

et al. 2017

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Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood–brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin–treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte–thrombin interaction may play a key role in causing BBB dysfunction in obesity-associated diabetes and represent a therapeutic target for its CNS complications.

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“…Real-time quantitative PCR was carried out as previously described [41]. The specific primer-probe sets for rat IL-1β, IL-6, TNF-α and GAPDH were purchased from Takara (Shiga, Japan).…”

Section: Methodsmentioning

confidence: 99%

Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model

et al. 2017

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“…It has been shown that TNF-α, IL-1β, and IFN-γ promote the expression of inducible nitric oxide synthase (iNOS) by porcine (36) and rat (51) brain PC. The generation of NO by PC can act in both an autocrine and paracrine manner as a relaxing factor, which leads to vasodilation.…”

Section: Pericyte Response To Pro-inflammatory Cuesmentioning

confidence: 99%

Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

et al. 2016

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Pericytes (PC) are mural cells that surround endothelial cells in small blood vessels. PC have traditionally been credited with structural functions, being essential for vessel maturation and stabilization. However, an accumulating body of evidence suggests that PC also display immune properties. They can respond to a series of pro-inflammatory stimuli and are able to sense different types of danger due to their expression of functional pattern-recognition receptors, contributing to the onset of innate immune responses. In this context, PC not only secrete a variety of chemokines but also overexpress adhesion molecules such as ICAM-1 and VCAM-1 involved in the control of immune cell trafficking across vessel walls. In addition to their role in innate immunity, PC are involved in adaptive immunity. It has been reported that interaction with PC anergizes T cells, which is attributed, at least in part, to the expression of PD-L1. As components of the tumor microenvironment, PC can also modulate the antitumor immune response. However, their role is complex, and further studies will be required to better understand the crosstalk of PC with immune cells in order to consider them as potential therapeutic targets. In any case, PC will be looked at with new eyes by immunologists from now on.

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“…The lack of effect of astrocyte-or RASM-derived soluble factors on insulin signaling in GT1-7 cells suggests that pericytes produce specific substances to enhance insulin signaling. We previously demonstrated that the baseline levels of monocyte chemotactic protein 1, macrophage inflammatory protein 1a and interleukin-6 released from pericytes were higher than those released from other cell types of the BBB [25]. Insulin sensitivity is increased by interleukin-6 in a concentrationdependent manner in the hypothalamus of exercised rats [26].…”

Section: Discussionmentioning

confidence: 97%

Brain pericyte-derived soluble factors enhance insulin sensitivity in GT1-7 hypothalamic neurons

Takahashi

Takata

Matsumoto

et al. 2015

Biochemical and Biophysical Research Communications

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Tumor necrosis factor-α-stimulated brain pericytes possess a unique cytokine and chemokine release profile and enhance microglial activation

Cited by 73 publications

References 28 publications

Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model

Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model

Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

Brain pericyte-derived soluble factors enhance insulin sensitivity in GT1-7 hypothalamic neurons

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