Reversal of prolonged obesity-associated cerebrovascular dysfunction by inhibiting microglial Tak1

Shen, Qing; Chen, Zhuo; Zhao, Fengbo; Pan, Susu; Zhang, Tingting; Cheng, Xueer; Zhang, Lei; Zhang, Shanshan; Qi, Junxia; Li, Juxue; Cai, Dongsheng; Zhang, Guo

doi:10.1038/s41593-020-0642-6

Cited by 24 publications

(21 citation statements)

References 54 publications

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“…These results suggest that TAK1 inhibition could reduce neuronal pyroptosis after SAH. A recent study reported that IL-18, which is induced by microglial TAK1 activation in the obese mouse brainstem, could act with the IL-18 receptor on endothelial cells to decrease the activity of eNOS, thereby resulting in endothelial dysfunction [ 45 ]. So, in our study, IL-18 secretion induced by neuronal pyroptosis might aggravate BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage

Tao

Zhu

et al. 2021

J Neuroinflammation

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Background Innate immunity can facilitate early brain injury (EBI) following subarachnoid hemorrhage (SAH). Numerous studies suggest that pyroptosis could exacerbate extracellular immune responses by promoting secretion of inflammatory cytokines. Transforming growth factor-β-activated kinase 1 (TAK1) is a quintessential kinase that positively regulates inflammation through NF-κB and MAPK signaling cascades. However, the effects of TAK1 on neuroinflammation in EBI following SAH are largely unknown. Methods Two hundred and forty-six male C57BL/6J mice were subjected to the endovascular perforation model of SAH. A selective TAK1 inhibitor, 5Z-7-oxozeaenol (OZ) was administered by intracerebroventricular (i.c.v) injection at 30 min after SAH induction. To genetic knockdown of TAK1, small interfering RNA (siRNA) was i.c.v injected at 48 h before SAH induction. SAH grade, brain water content, BBB permeability, neurological score, western blot, real-time PCR, ELISA, transmission electron microscope, and immunofluorescence staining were performed. Long-term behavioral sequelae were evaluated by the rotarod and Morris water maze tests. Furthermore, OZ was added to the culture medium with oxyhemoglobin (OxyHb) to mimic SAH in vitro. The reactive oxygen species level was detected by DCFH-DA staining. Lysosomal integrity was assessed by Lyso-Tracker Red staining and Acridine Orange staining. Results The neuronal phosphorylated TAK1 expression was upregulated following SAH. Pharmacologic inhibition of TAK1 with OZ could alleviate neurological deficits, brain edema, and brain-blood barrier (BBB) disruption at 24 h after SAH. In addition, OZ administration restored long-term neurobehavioral function. Furthermore, blockade of TAK1 dampened neuronal pyroptosis by downregulating the N-terminal fragment of GSDMD (GSDMD-N) expression and IL-1β/IL-18 production. Mechanistically, both in vivo and in vitro, we demonstrated that TAK1 can induce neuronal pyroptosis through promoting nuclear translocation of NF-κB p65 and activating nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. TAK1 siRNA treatment mitigated SAH-induced neurobehavioral deficits and restrained phosphorylated NF-κB p65 expression and NLRP3 inflammasome activation. TAK1 blockade also ameliorated reactive oxygen species (ROS) production and prevented lysosomal cathepsin B releasing into the cytoplasm. Conclusions Our findings demonstrate that TAK1 modulates NLRP3-mediated neuronal pyroptosis in EBI following SAH. Inhibition of TAK1 may serve as a potential candidate to relieve neuroinflammatory responses triggered by SAH.

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Section: Discussionmentioning

confidence: 99%

TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage

Tao

Zhu

et al. 2021

J Neuroinflammation

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“…The detailed procedures have been described previously (Shen et al, 2020). Mice were anaesthetized using Avertin, and then were transcardially perfused with 4% PFA.…”

Section: Immunofluorescencementioning

confidence: 99%

Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice

Pan

Yin

Tang

et al. 2021

eLife

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Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, eg. celastrol, might be a novel strategy for colorectal cancer treatment.

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“…This may not only provide novel treatment options for chronic diseases with a direct manifestation at entheses such as spondyloarthropathies but also to additional chronic comorbidities such as metabolic diseases. As one example, it was demonstrated that reversal of prolonged obesity-associated cerebrovascular dysfunction could be achieved by inhibiting TAK1 in microglial cells (macrophages within brain [ 74 ]). Since comorbidities such as cardiovascular disease, obesity or diabetes mellitus may notably influence the course of disease and treatment response this stresses the need for novel treatment strategies in the musculoskeletal system and beyond [ 75 , 76 ].…”

Section: Inflammation and The Immune System At Enthesesmentioning

confidence: 99%

Regeneration of Damaged Tendon-Bone Junctions (Entheses)—TAK1 as a Potential Node Factor

Friese

Gierschner

Schadzek

et al. 2020

IJMS

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Musculoskeletal dysfunctions are highly prevalent due to increasing life expectancy. Consequently, novel solutions to optimize treatment of patients are required. The current major research focus is to develop innovative concepts for single tissues. However, interest is also emerging to generate applications for tissue transitions where highly divergent properties need to work together, as in bone-cartilage or bone-tendon transitions. Finding medical solutions for dysfunctions of such tissue transitions presents an added challenge, both in research and in clinics. This review aims to provide an overview of the anatomical structure of healthy adult entheses and their development during embryogenesis. Subsequently, important scientific progress in restoration of damaged entheses is presented. With respect to enthesis dysfunction, the review further focuses on inflammation. Although molecular, cellular and tissue mechanisms during inflammation are well understood, tissue regeneration in context of inflammation still presents an unmet clinical need and goes along with unresolved biological questions. Furthermore, this review gives particular attention to the potential role of a signaling mediator protein, transforming growth factor beta-activated kinase-1 (TAK1), which is at the node of regenerative and inflammatory signaling and is one example for a less regarded aspect and potential important link between tissue regeneration and inflammation.

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Reversal of prolonged obesity-associated cerebrovascular dysfunction by inhibiting microglial Tak1

Cited by 24 publications

References 54 publications

TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage

TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage

Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice

Regeneration of Damaged Tendon-Bone Junctions (Entheses)—TAK1 as a Potential Node Factor

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