scholarly journals Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

2021 ◽  
Author(s):  
XIN LIU ◽  
Chilman Bae ◽  
Bolong Liu ◽  
Yongmei Zhang ◽  
Xiangfu Zhou ◽  
...  
Keyword(s):  
Neural Circuit ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Opioid Analgesics ◽  
Reactive Astrocytes ◽  
Opioid Overdose ◽  
Knock Out ◽  
Genetic Ablation ◽  
Opioid Induced Hyperalgesia

Opioid analgesics are the frontline pain medicine for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH). OIH significantly contributes to dose escalation and consequently opioid overdose. In addition to neuronal malplasticity, emerging evidence suggests a critical role of reactive glia in OIH development. A potential astrocytic underpinning of OIH pathogenesis is indicated by their prominently activation in OIH animal models. However, this hypothesis has not been conclusively tested and the mechanism underlying the astrocyte activation remains unclear. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in mice. Genetic ablation of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We also found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1β. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.

scholarly journals Differences in chloride gradients allow for three distinct types of synaptic modulation by endocannabinoids

2016 ◽  
Vol 116 (2) ◽  
pp. 619-628 ◽  
Author(s):  
Yanqing Wang ◽  
Brian D. Burrell
Keyword(s):  
Neural Circuit ◽  
Critical Role ◽  
Low Frequency ◽  
Inhibitory Synapses ◽  
Primary Role ◽  
Synaptic Modulation ◽  
Hirudo Verbana ◽  
Frequency Stimulation ◽  
Circuit Output

Endocannabinoids can elicit persistent depression of excitatory and inhibitory synapses, reducing or enhancing (disinhibiting) neural circuit output, respectively. In this study, we examined whether differences in Cl−gradients can regulate which synapses undergo endocannabinoid-mediated synaptic depression vs. disinhibition using the well-characterized central nervous system (CNS) of the medicinal leech, Hirudo verbana. Exogenous application of endocannabinoids or capsaicin elicits potentiation of pressure (P) cell synapses and depression of both polymodal (Npoly) and mechanical (Nmech) nociceptive synapses. In P synapses, blocking Cl−export prevented endocannabinoid-mediated potentiation, consistent with a disinhibition process that has been indicated by previous experiments. In Nmechneurons, which are depolarized by GABA due to an elevated Cl−equilibrium potentials (ECl), endocannabinoid-mediated depression was prevented by blocking Cl−import, indicating that this decrease in synaptic signaling was due to depression of excitatory GABAergic input (disexcitation). Npolyneurons are also depolarized by GABA, but endocannabinoids elicit depression in these synapses directly and were only weakly affected by disruption of Cl−import. Consequently, the primary role of elevated EClmay be to protect Npolysynapses from disinhibition. All forms of endocannabinoid-mediated plasticity required activation of transient potential receptor vanilloid (TRPV) channels. Endocannabinoid/TRPV-dependent synaptic plasticity could also be elicited by distinct patterns of afferent stimulation with low-frequency stimulation (LFS) eliciting endocannabinoid-mediated depression of Npolysynapses and high-frequency stimulus (HFS) eliciting endocannabinoid-mediated potentiation of P synapses and depression of Nmechsynapses. These findings demonstrate a critical role of differences in Cl−gradients between neurons in determining the sign, potentiation vs. depression, of synaptic modulation under normal physiological conditions.

scholarly journals EPC1/TIP60-Mediated Histone Acetylation Facilitates Spermiogenesis in Mice

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Yixin Dong ◽  
Kyo-ichi Isono ◽  
Kazuyuki Ohbo ◽  
Takaho A. Endo ◽  
Osamu Ohara ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Germ Cells ◽  
Essential Role ◽  
Critical Role ◽  
Male Germ Cells ◽  
Genetic Ablation ◽  
Histone Hyperacetylation ◽  
Critical Components ◽  
Underlying Mechanisms

ABSTRACT Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation-mediated histone replacement remains poorly understood. Here, we report that EPC1 and TIP60, two critical components of the mammalian nucleosome acetyltransferase of H4 (NuA4) complexes, are coexpressed in male germ cells. Strikingly, genetic ablation of either Epc1 or Tip60 disrupts hyperacetylation and impairs histone replacement, in turn causing aberrant spermatid development. Taking these observations together, we reveal an essential role of the NuA4 complexes for histone hyperacetylation and subsequent compaction of the spermatid genome.

scholarly journals Microglial ablation does not affect opioid-induced hyperalgesia in rodents

2021 ◽  
Author(s):  
Xin Liu ◽  
Bo-Long Liu ◽  
Qing Yang ◽  
Xiangfu Zhou ◽  
Shao-Jun Tang
Keyword(s):  
Critical Role ◽  
Thermal Hyperalgesia ◽  
Opioid Analgesics ◽  
Diphtheria Toxin Receptor ◽  
Opioid Induced Hyperalgesia ◽  
Toxin Receptor ◽  
Stimulating Factor ◽  
Chronic Use ◽  
Term Management

AbstractOpioids are the frontline analgesics in pain management. However, chronic use of opioid analgesics causes paradoxical pain that contributes to the decrease of their efficacy in pain control and the escalation of dose in long-term management of pain. The underling pathogenic mechanism is not well understood. Microglia have been commonly thought to play a critical role in the expression of opioid-induced hyperalgesia (OIH) in animal models. We performed microglial ablation experiments using either a genetic (CD11b-diphtheria toxin receptor transgenic mouse) or pharmacological (colony-stimulating factor 1 receptor inhibitor PLX5622) approaches. Surprisingly, ablating microglia using these specific and effective approaches did not cause detectable impairment in the expression of hyperalgesia induced by morphine. We confirmed this conclusion with behavioral test of mechanical and thermal hyperalgesia, in male and female mice, and with different species (mouse and rat). These findings raise caution about the widely assumed contribution of microglia to the development of OIH.

Abstract 420: Mrs2 is the Authentic Mammalian Mitochondrial Mg 2+ Channel

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Prema Velusamy ◽  
Shanmughapriya Santhanam
Keyword(s):  
Copy Number ◽  
Mitochondrial Permeability Transition ◽  
Critical Role ◽  
Permeability Transition ◽  
Inner Mitochondrial Membrane ◽  
Metabolic Switch ◽  
Knock Out ◽  
Mitochondrial Copy Number

Magnesium (Mg 2+ ) is an important cation critical for cellular functions and tissue integrity. Mitochondria have been demonstrated to be capable of both accumulate and release Mg 2+ . However, the exact molecular machinery associated with mitochondrial Mg 2+ (mMg 2+ ) influx has not yet been delineated. In the present study we characterized the mammalian mMg 2+ channel, Mrs2 and comprehensively studied its role in energy metabolism. Protein flux, membrane fractionation and STED microscopy studies revealed Mrs2 to localize on the inner mitochondrial membrane with its N and C-terminus in the matrix. Western blot and qPCR analysis confirmed the ubiquitous distribution of Mrs2 in all metabolically active tissues. We adopted lentiviral based strategy to stably knock down (KD) Mrs2 in vitro . Primarily, the use of FRET-based mMg 2+ sensor, MitoMario showed a decreased influx of Mg 2+ into mitochondria in Mrs2 KD cells. This was further confirmed by patch clamping the mitoplasts of the control and Mrs2 KD cells. Because Mg 2+ is an important co-factor in the machineries that replicate, we next assessed the mitochondrial copy number. The decreased influx of mMg 2+ impacted the mitochondrial copy number and electron transport chain (ETC) complex assembly. The defective ETC assembly was marked by increased generation of mitochondrial reactive oxygen species, increased proton leak, decreased ATP levels, and also prompted a metabolic switch from mitochondrial oxidative phosphorylation to glucose oxidation in Mrs2 KD cells. Additionally, Mrs2 KD cells had an increased sensitivity to mROS-induced mitochondrial permeability transition pore opening. To further study the role of Mrs2 in cardiac mitochondrial metabolism and cellular energetics, we have successfully adopted the CRISPR/Cas9 mediated gene targeting strategy to generate the cardiac-specific Mrs2 knock out mouse model. Our study is the first of its kind to characterize the mitochondrial Mg 2+ channel and its impact on mitochondrial copy number and cell viability. Our findings not only identify Mrs2 as an authentic mitochondrial Mg 2+ channel, but also validates the critical role of mMg 2+ in maintaining the bioenergetic state of the cell.

scholarly journals Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Weilin Zhang ◽  
He Ren ◽  
Chunling Xu ◽  
Chongzhuo Zhu ◽  
Hao Wu ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Acute Ischemia ◽  
Dependent Manner ◽  
Genetic Ablation ◽  
A Cell ◽  
Novel Strategy

Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.

scholarly journals Midkine-a regulates the formation of a fibrotic scar during zebrafish heart regeneration

2021 ◽  
Author(s):  
Dimitrios Grivas ◽  
Álvaro González-Rajal ◽  
José Luis de la Pompa
Keyword(s):  
Critical Role ◽  
Cardiac Injury ◽  
Transcriptional Analysis ◽  
Endothelial Cell Proliferation ◽  
Heart Regeneration ◽  
Knock Out ◽  
Tgfβ Signalling ◽  
Fibrotic Scar ◽  
Zebrafish Heart

AbstractThe adult zebrafish heart regenerates after injury, unlike the hearts of mammals. Heart cryoinjury triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of mdka in zebrafish heart regeneration. We show that mdka expression is strongly induced at 1-day post cryoinjury (dpci) throughout the epicardium, whereas by 7 dpci expression has become restricted to epicardial cells covering the injured area. To study the role of mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka decreased endothelial cell proliferation and resulted in a blockade of heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and TGFβ signalling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.

scholarly journals The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

2020 ◽  
Author(s):  
Fan Huang ◽  
Christophe Gonçalves ◽  
Margarita Bartish ◽  
Joelle Rémy-Sarrazin ◽  
Qianyu Guo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Critical Role ◽  
Inflammatory Factors ◽  
Genetic Ablation ◽  
Immune Exhaustion ◽  
New Strategy ◽  
Phenotype Switch ◽  
Phenotype Switching ◽  
Immunosuppressive Microenvironment

AbstractMelanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Melanoma plasticity exhibited as phenotype switching contributes to immunotherapy resistance, however the mechanisms are not completely understood and thus therapeutically unexploited. Here, using a transgenic melanoma mouse model, we demonstrated a critical role of the MNK1/2-eIF4E axis in melanoma plasticity and resistance to immunotherapy. We showed that phospho-eIF4E deficient murine melanomas express high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified that phospho-eIF4E controls the translation of NGFR, a critical effector of phenotype switching. In patients with melanoma, the expression of MKNK1, the kinase for eIF4E, positively correlated with markers of immune exhaustion. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors and increased CD8+ T cell infiltrates. Blocking phospho-eIF4E, using MNK1/2 inhibitors, offers a new strategy to inhibit melanoma plasticity and improve the survival response to anti-PD-1 immunotherapy.

scholarly journals Midkine-a Regulates the Formation of a Fibrotic Scar During Zebrafish Heart Regeneration

2021 ◽  
Vol 9 ◽  
Author(s):  
Dimitrios Grivas ◽  
Álvaro González-Rajal ◽  
José Luis de la Pompa
Keyword(s):  
Critical Role ◽  
Cardiac Injury ◽  
Transcriptional Analysis ◽  
Endothelial Cell Proliferation ◽  
Heart Regeneration ◽  
Knock Out ◽  
Injured Area ◽  
Fibrotic Scar ◽  
Zebrafish Heart

Unlike the hearts of mammals, the adult zebrafish heart regenerates after injury. Heart cryoinjury in zebrafish triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of mdka in zebrafish heart regeneration. We show that mdka expression was induced at 1-day post-cryoinjury (dpci) throughout the epicardial layer, whereas by 7 dpci expression had become restricted to the epicardial cells covering the injured area. To study the role of mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka decreased endothelial cell proliferation and resulted in an arrest in heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and intense TGFβ signaling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.

scholarly journals Complement Factor C7 Contributes to Lung Immunopathology Caused byMycobacterium tuberculosis

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Kerry J. Welsh ◽  
Cole T. Lewis ◽  
Sydney Boyd ◽  
Michael C. Braun ◽  
Jeffrey K. Actor
Keyword(s):  
Post Infection ◽  
Critical Role ◽  
Complement Factor ◽  
Wild Type ◽  
Knock Out ◽  
Host Protection ◽  
Colony Forming Units ◽  
Knock Out Mice ◽  
The Complement System

Mycobacterium tuberculosis(MTB) remains a significant global health burden despite the availability of antimicrobial chemotherapy. Increasing evidence indicates a critical role of the complement system in the development of host protection against the bacillus, but few studies have specifically explored the function of the terminal complement factors. Mice deficient in complement C7 and wild-type C57BL/6 mice were aerosol challenged with MTB Erdman and assessed for bacterial burden, histopathology, and lung cytokine responses at days 30 and 60 post-infection. Macrophages isolated from C7 −/− and wild-type mice were evaluated for MTB proliferation and cytokine production. C7 −/− mice had significantly less liver colony forming units (CFUs) at day 30; no differences were noted in lung CFUs. The C7 deficient mice had markedly reduced lung occlusion with significantly increased total lymphocytes, decreased macrophages, and increased numbers of CD4+ cells 60 days post-infection. Expression of lung IFN-γand TNF-αwas increased at day 60 compared to wild-type mice. There were no differences in MTB-proliferation in macrophages isolated from wild-type and knock-out mice. These results indicate a role for complement C7 in the development of MTB induced immunopathology which warrants further investigation.

scholarly journals Oligodendrocytes Development and Wnt Signaling Pathway

2018 ◽  
Vol 1 (3) ◽  
pp. 17-35 ◽  
Author(s):  
Shahid Hussain Soomro ◽  
Jifu Jie ◽  
Hui Fu
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Developmental Stages ◽  
Critical Role ◽  
Wnt Signaling Pathway ◽  
Study Groups ◽  
Multiple Roles ◽  
Proliferation And Differentiation ◽  
Early Developmental

Oligodendrocytes are specialized glial cell in central nervous system (CNS) responsible for the formation of myelin sheath around the axon. Oligodendrocyte proliferation and differentiation is regulated by Wnt signaling pathway, at various stages. However, different study groups have described controversial conclusions about the effect of Wnt on oligodendrocytes precursor cells (OPCs) development. Initially it has been proposed that Wnt pathway negatively regulates the OPCs proliferation and differentiation but recently some studies have described that Wnt promotes the differentiation of OPCs. After carefully reviewing the literature, we believe that Wnt play multiple roles in OPCs differentiation and its function is time (stage) and dose sensitive. Low to moderate activation of Wnt promotes OPC development, while too much or too low is inhibitory. Current evidences also suggested that in early developmental stages, Wnt inhibits the OPCs formation from neural progenitors and differentiation into immature oligodendrocytes. But in late stages Wnt plays promoting role in differentiation and maturation of oligodendrocytes. This review summarized the updated information regarding the critical role of Wnt signaling cascade in proliferation and differentiation of OPCs.

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