The Latest Articles on Neuroinflammation

Our staff editors continue to share exciting, interesting, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several latest articles on Neuroinflammation.

Title: Impact of neuroinflammation on epigenetic transcriptional control of Sonic Hedgehog members in the central nervous system
Authors: Mariana Ribeiro Costa, Amanda Yasmin Ilario dos Santos, Taís Browne de Miranda, Alex de Camargo Coque, Elizabeth Cristina Perez Hurtado, Maria Martha Bernardi, Vanessa Gallego Arias Pecorari, Denise Carleto Andia, Alexander Birbrair, Gilles J. Guillemin, Alexandra Latini, Rodrigo A. da Silva
Type: Research Article
Abstract:
Sonic Hedgehog (Shh) signaling plays a critical role during central nervous system (CNS) development, and its dysregulation leads to neurological disorders. Nevertheless, little is known about Shh signaling regulation in the adult brain. Here, we investigated the contribution of DNA methylation on the transcriptional control of Shh signaling pathway members and its basal distribution impact on the brain, as well as its modulation by inflammation. The methylation status of the promoter regions of these members and the transcriptional profile of DNA-modifying enzymes (DNA Methyltransferases – DNMTs and Tet Methylcytosine Dioxygenase – TETs) were investigated in a murine model of neuroinflammation by qPCR. We showed that, in the adult brain, methylation in the CpG promoter regions of the Shh signaling pathway members was critical to determine the endogenous differential transcriptional pattern observed between distinct brain regions. We also found that neuroinflammation differentially modulates gene expression of DNA-modifying enzymes. This study reveals the basal transcriptional profile of DNMTs and TETs enzymes in the CNS and demonstrates the effect of neuroinflammation on the transcriptional control of members of the Shh Signaling pathway in the adult brain.
Access this article: https://doi.org/10.1016/j.brainres.2022.148180

Title: YAP/TFRC/ALOXE3 signaling is involved in ferroptosis and neuroinflammation triggered by amino-functionalized graphene quantum dots
Authors: Tianshu Wu, Xinyu Wang, Min Chen, Xiaomeng Zhang, Jixiang Zhang, Xuqing Fan, Yunbo Yu, Wenxin Zheng, Supu Maitiyv, Supu Maitiyv, Yán Wāng, Lu Kong, Meng Tang
Type: Research Article
Abstract:
Recently, graphene quantum dots (GQDs) have been attracting extensive interests in a widespread application, but the little information on the risk assessments of GQDs could impose a restriction on their contributions in the neuroscience. In this study, the intranasal administration of amino group functionalized GQDs (A-GQDs) was observed to enhance the number of neuronal cell death, trigger ferroptosis activities, i.e. ferrous iron overload and lipid peroxidation as well as cause inflammatory reactions in hippocampus. Meanwhile, these adverse effects were found in BV2 microglial cells treated with A-GQDs, which were all attenuated by a ferroptosis-specific inhibitor ferrostain-1 (Fer-1). The inflammatory responses to A-GQDs in BV2 cells were evidenced as the increased secretion of pro-inflammatory cytokine TNF-α that was attributed to the high mobility group box 1 (HMGB1) released from ferroptosis-occurred cells. The nuclear transference of yes-associated protein (YAP), an effector in Hippo signaling pathway, regulated by the phosphorylation of p38 mitogen-activated protein kinase (MAPK) was then found to play a critical role in A-GQDs triggering ferroptosis through transcriptionally mediating transferrin receptor protein (TFRC) and arachidonate lipoxygenase 3 (ALOXE3) to increase levels of ferrous iron and lipid peroxides, respectively. The findings not only highlight the importance of risk assessments on QDs containing low toxic component, but also provide toxic biomarkers for the interventions of GQDs in the brain.
Access this article: https://doi.org/10.1016/j.nantod.2022.101703

Title: Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke
Authors: Baoyi Chen, Cong Xie, Tengrui Shi, Shiqin Yue, Weiping Li, Guodong Huang, Yuan Zhang, Wenlan Liu
Type: Research Article
Abstract:
Cl− movement and Cl−-sensitive signal pathways contributes to the survival and switch of inflammatory phenotype of microglia and are believed to play a key role in the inflammatory brain injury after ischemic stroke. Here, we demonstrated an important role of Cl− transmembrane transporter Swell1, in the survival and M2-like polarization of microglia in ischemic stroke. Knockdown or overexpression of Swell1 in cultured microglia inhibited or increased hypotonic-activated Cl− currents, respectively, and these changes were completely blocked by the volume-regulated anion channels (VRACs) inhibitor DCPIB. Swell1 conditional knock-in mice promoted microglia survival in ischemic brain region and resulted in significant reductions in neural cell death, infarction volume and neurological deficits following transient middle cerebral artery occlusion (tMCAO). Using gene manipulating technique and pharmacological inhibitors, we further revealed that Swell1 opening led to SGK1 (a Cl−-sensitive kinase)-mediated activation of FOXO3a/CREB as well as WNK1 (another Cl−-sensitive kinase)-mediated SPAK/OSR1-CCCs activation, which promoted microglia survival and M2-like polarization, thereby attenuating neuroinflammation and ischemic brain injury. Taken together, our results demonstrated that Swell1 is an essential component of microglia VRACs and its activation protects against ischemic brain injury through promoting microglia survival and M2-like polarization.
Access this article: https://doi.org/10.1016/j.nbd.2022.105936

Title: Mesencephalic astrocyte-derived neurotrophic factor (MANF) prevents the neuroinflammation induced dopaminergic neurodegeneration
Authors: Jing-Xing Zhang, Kai-Ge Zhou, Yan-Xin Yin, Ling-Jing Jin, Wei-Fang Tong, Jia Guo, Li-Hua Yu, Xian-Cheng Ye, Ming Jiang
Type: Research Article
Abstract:
Background
The excessive activation of the microglia leads to the release of inflammatory factors that contribute to neuronal cell loss and neurodegeneration in Parkinson's Disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) that belongs to a newly found neurotrophic factors (NTFs) family has been reported to promote neuronal survival in the PD models. However, the effects of the MANF on neuroinflammation in PD remain unclear.

Methods
AAV8-MANF virus was constructed to determine whether the high expression of MANF can protect the neuroinflammation-induced dopaminergic neurodegeneration in rats with 6-OHDA-induced PD. Rotarod performance test, immunofluorescent staining and western bolt were employed to evaluate the behavioral dysfunction, dopaminergic neurodegeneration, microglia activation, and signal activation. 6-OHDA treated SH-SY5Y cells and LPS treated BV-2 cells were used as the in vitro model for MANF neuroprotective and neuroinflammation mechanisms. Cell vitality and apoptosis were evaluated with MTT, CCK-8 and flow cytometric analysis. The AKT/GSK3β-Nrf2 signaling and the TNF-α/IL6 expression were measured by Western Blot.

Results
Our findings indicated that the elevated MANF expression by the AAV8-MANF administration ameliorated the motor dysfunction and protected the dopaminergic neurons in the 6-OHDA treated rats. The upregulated CD11b in the rat SN caused by the 6-OHDA administration was significantly attenuated by the pretreatment of the AAV8-MANF. Furthermore, the levels of p-AKT, p-GSK3β, BCL-2, and Nrf-2 were upregulated by the high expression of the MANF. Under the oxidative stress of the 6-OHDA, the MANF significantly reduced the apoptotic effect of the TNF-α on the SH-SY5Y cells. In the LPS treated BV-2 cells, the MANF reduced the production of the TNF-α and IL-6, via enhancing the Nrf-2, p-Akt, p-GSK3β, and p-NF-κβ level.

Conclusions
These results suggested that the MANF prevented the dopaminergic neurodegeneration caused by the microglia activation in PD via activation of the AKT/GSK3β-Nrf-2 signaling axis.
Access this article: https://doi.org/10.1016/j.exger.2022.112037

Title: Secukinumab attenuates neuroinflammation and neurobehavior defect via PKCβ/ERK/NF-κB pathway in a rat model of GMH
Authors: Shengpeng Liu, Shuixiang Deng, Yan Ding, Jerry J. Flores, Xiaoli Zhang, Xiaojing Jia, Xiao Hu, Jun Peng, Gang Zuo, John H. Zhang, Ye Gong, Jiping Tang
Type: Research Article
Abstract:
Aims
Germinal matrix hemorrhage (GMH) is a disastrous clinical event for newborns. Neuroinflammation plays an important role in the development of neurological deficits after GMH. The purpose of this study is to investigate the anti-inflammatory role of secukinumab after GMH and its underlying mechanisms involving PKCβ/ERK/NF-κB signaling pathway.

Methods
A total of 154 Sprague-Dawley P7 rat pups were used. GMH was induced by intraparenchymal injection of bacterial collagenase. Secukinumab was administered intranasally post-GMH. PKCβ activator PMA and p-ERK activator Ceramide C6 were administered intracerebroventricularly at 24 h prior to GMH induction, respectively. Neurobehavioral tests, western blot and immunohistochemistry were used to evaluate the efficacy of Secukinumab in both short-term and long-term studies.

Results
Endogenous IL-17A, IL-17RA, PKCβ and p-ERK were increased after GMH. Secukinumab treatment improved short- and long-term neurological outcomes, reduced the synthesis of MPO and Iba-1 in the perihematoma area, and inhibited the synthesis of proinflammatory factors, such as NF-κB, IL-1β, TNF-α and IL-6. Additionally, PMA and ceramide C6 abolished the beneficial effects of Secukinumab.

Conclusion
Secukinumab treatment suppressed neuroinflammation and attenuated neurological deficits after GMH, which was mediated through the downregulation of the PKCβ/ERK/NF-κB pathway. Secukinumab treatment may provide a promising therapeutic strategy for GMH patients.
Access this article: https://doi.org/10.1016/j.expneurol.2022.114276