Brain-derived neurotrophic factor fused with a collagen-binding domain inhibits neuroinflammation and promotes neurological recovery of traumatic brain injury mice via TrkB signalling

Yin, Rui; Zhao, Shufa; Qiu, Caixia

doi:10.1111/jphp.13233

Cited by 32 publications

(17 citation statements)

References 33 publications

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“…Therefore, the HMGB1/TLR4/NF-κB pathway is closely associated with the pyroptosis. It also has been mentioned that neuronal death and neurological deficits are closely associated with inflammatory response in TBI [59]. In this study, the results indicated that VX765 can dampen the inflammatory response by attenuating the HMGB1/TLR4/NF-κB signaling pathway in a mouse TBI model.…”

Section: Discussionmentioning

confidence: 52%

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

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Section: Discussionmentioning

confidence: 52%

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Other cytokine and cytokine receptor genes that continued to have consistent dysregulation with complement inhibition include Ccl3 , Csf1 , Csf3r , Cxcl10 , Il21r , and Tnfrsf25 . Moreover, we found the neurotropic factor, Bdnf , and the glutamatergic synapse regulators, Homer1 and Pacsin1 , remained downregulated, suggesting that adjuvant treatment with exogenous Bdnf, shown to be beneficial after TBI [ 43 ], might boost the neuroprotective effects of CR2-Crry on synaptic rescue and functional outcomes. Finally, at day 28 pi, there was upregulation of genes encoding several markers of reactive astrocytes (Cxcl10, Gbp2, Psmb8, Cd109, Tgm1) [ 20 ], reactive oligodendrocytes (C4a, Serpina3n) [ 44 ], and disease-associated microglia (Apoe, Axl, Clec7a, Tyrobp, Trem2) [ 30 ], indicating persistent, despite reduced, cellular inflammation with complement inhibition.…”

Section: Resultsmentioning

confidence: 99%

Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

Toutonji

Mandava

Guglietta

et al. 2021

acta neuropathol commun

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Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

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“…Microglia, the resident immune cells of the CNS, contribute in a major way to the regulation of inflammation [ 1 ]. They function as a crucial defence against various types of insult to tissues and cells within the brain [ 2 , 3 ], with the ability to exist in either a resting state (ramified) or an active state (amoeboid) [ 4 ]. In the case of inflammation, infection or trauma, microglia rapidly convert into an activated state and become phagocytic [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…They function as a crucial defence against various types of insult to tissues and cells within the brain [ 2 , 3 ], with the ability to exist in either a resting state (ramified) or an active state (amoeboid) [ 4 ]. In the case of inflammation, infection or trauma, microglia rapidly convert into an activated state and become phagocytic [ 3 ]. Also, whilst in an active state, microglia can secrete both pro- and anti-inflammatory cytokines, the latter including interleukin 10 (IL-10) and transforming growth factor β (TGF-β) [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia

Goudarzi

Gilchrist

Hafizi

2020

Cells

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The Gas6–TAM (Tyro3, Axl, Mer) ligand–receptor system is believed to promote central nervous system (CNS) (re)myelination and glial cell development. An additional important function of Gas6–TAM signalling appears to be the regulation of immunity and inflammation, which remains to be fully elucidated in the CNS. Here, we characterised the expression of TAM receptors and ligands in individual CNS glial cell types, observing high expression of Gas6 and the TAM receptors, Mer and Axl, in microglia, and high expression of Tyro3 in astrocytes. We also investigated the effect of Gas6 on the inflammatory cytokine response in the optic nerve and in mixed glial cell cultures from wildtype and single TAM receptor knockout mice. In wildtype and Mer-deficient cultures, Gas6 significantly stimulated the expression of the anti-inflammatory/pro-repair cytokines interleukin 10 (IL-10) and transforming growth factor β (TGF-β), whereas this effect was absent in either Tyro3 or Axl knockout cultures. Furthermore, Gas6 caused upregulation of myelin basic protein (MBP) expression in optic nerves, which was blocked by a neutralising antibody against IL-10. In conclusion, our data show that microglia are both a major source of Gas6 as well as an effector of Gas6 action in the CNS through the upregulation of anti-inflammatory and pro-repair mediators. Furthermore, the presence of both Axl and Tyro3 receptors appears to be necessary for these effects of Gas6. In addition, IL-10, alongside suppressing inflammation and immunity, mediates the pro-myelinating mechanism of Gas6 action in the optic nerve. Therefore, Gas6 may present an attractive target for novel therapeutic interventions for demyelinating as well as neuroinflammatory disorders of the CNS.

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Brain-derived neurotrophic factor fused with a collagen-binding domain inhibits neuroinflammation and promotes neurological recovery of traumatic brain injury mice via TrkB signalling

Cited by 32 publications

References 33 publications

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

Gas6 Induces Myelination through Anti-Inflammatory IL-10 and TGF-β Upregulation in White Matter and Glia

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