Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β

Frontiers in Pain Research, Год журнала: 2021, Номер 2

Опубликована: Авг. 25, 2021

Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast fibroblasts, keratinocytes and epithelial cells activated leading to the generation an "inflammatory soup" containing cytokines, chemokines growth factors. These primary mediators sensitize sensory endings, attract macrophages, neutrophils lymphocytes, alter gene expression, promote post-translational modification proteins, ion channel function in afferent neurons. This leads increased excitability spontaneous activity secondary including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, Wnt5a. Release these from neurons alters properties spinal microglial causing them release tertiary mediators, many situations

Язык: Английский

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Neuropathic pain; what we know and what we should do about it

Frontiers in Pain Research, Год журнала: 2023, Номер 4

Опубликована: Сен. 22, 2023

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve promotes Schwann cell activation and invasion immunocompetent cells into site injury, spinal cord higher sensory structures such as thalamus cingulate cortices. Various cytokines, chemokines, growth factors, monoamines neuropeptides effect two-way signalling between neurons, glia immune cells. This sustained hyperexcitability spontaneous activity in primary afferents that crucial for onset persistence well misprocessing information supraspinal structures. Much current understanding aetiology identification drug targets derives studies consequences peripheral rodent models. Although a vast amount has been forthcoming, translation this clinical arena minimal. Few, if any, major therapeutic approaches have appeared since mid 1990's. may reflect failure recognise differences processing males vs. females, cellular responses different types humans animals. Basic science which seek bridge knowledge gap include better assessment animal models, use models emulate human disease, stratification phenotypes according quantitative signs symptoms disease. lead more personalized effective treatments individual patients. Significance statement: There an urgent need find new neuropathic pain. classical revealed essential features central sensitization some molecular mechanisms involved, they do not adequately model multiplicity states injuries bring forth clinic. review seeks integrate disciplines understand pain; including immunology, biology, electrophysiology biophysics, anatomy, neurology, pharmacology behavioral science. Beyond this, it underlines ongoing refinements basic practice will engender improved management.

Язык: Английский

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Neuroinflammation generated by HIV-infected microglia promotes dysfunction and death of neurons in human brain organoids

PNAS Nexus, Год журнала: 2024, Номер 3(5)

Опубликована: Апрель 29, 2024

Abstract Despite the success of combination antiretroviral therapy (ART) for individuals living with HIV, mild forms HIV-associated neurocognitive disorder (HAND) continue to occur. Brain microglia form principal target HIV infection in brain. It remains unknown how these cells leads neuroinflammation, neuronal dysfunction, and/or death observed HAND. Utilizing two different inducible pluripotent stem cell-derived brain organoid models (cerebral and choroid plexus [ChP] organoids) containing microglia, we investigated pathogenic changes associated infection. Infection was a sharp increase CCL2 CXCL10 chemokine gene expression activation many type I interferon stimulated genes (MX1, ISG15, ISG20, IFI27, IFITM3 others). Production proinflammatory chemokines persisted at low levels after treatment cell cultures ART, consistent persistence HAND following clinical introduction ART. Expression multiple members S100 family inflammatory sharply increased measured by single-cell RNA-seq. However, not limited but also detected more broadly uninfected stromal cells, mature immature ChP neural progenitor importantly bystander neurons suggesting propagation response cells. Neurotransmitter transporter declined neurons, accompanied promoting cellular senescence death. Together, studies underscore an generated HIV-infected is propagated ultimately resulting dysfunction neurons.

Язык: Английский

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PKR Inhibitor C16 Regulates HIV-gp120 Induced Neuronal Injury and Cognitive Impairment in Vivo and in Vitro Models

Neurochemical Research, Год журнала: 2025, Номер 50(1)

Опубликована: Янв. 3, 2025

Язык: Английский

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Microglia and Wnt Pathways: Prospects for Inflammation in Alzheimer’s Disease

Frontiers in Aging Neuroscience, Год журнала: 2020, Номер 12

Опубликована: Май 14, 2020

Alzheimer's disease (AD) has been a major health issue for more than one century since it was first reported in 1906. As of the most common neurodegenerative diseases, AD is characterized by presence senile plaques and neurofibrillary tangles (NFTs) affected brain area. Microglia are regulator neuroinflammation brain, core pathophysiological process various diseases. In central nervous system (CNS), microglia play dual role development. For thing, they degrade amyloid β (Aβ) to resist its deposition; another, release pro-inflammatory inflammatory factors, contribute as well spreading Aβ tau pathology. Wnt pathways important regulators cell fate activities. The dysregulation responsible both abnormal phosphorylation synaptic loss AD. Recent studies have also confirmed regulatory effect signaling on microglial inflammation. Thus, microglia, their possible interactions may open up new direction underlying mechanisms this review, we summarize function pathways, roles order provide ideas understanding pathogenesis

Язык: Английский

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Single-cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia

iScience, Год журнала: 2021, Номер 24(3), С. 102186 - 102186

Опубликована: Фев. 16, 2021

Microglia are ubiquitous central nervous system (CNS)-resident macrophages that maintain homeostasis of neural tissues and protect them from pathogen attacks. Yet, their differentiation in different compartments remains elusive. We performed single-cell RNA-seq to compare microglial subtypes the cortex spinal cord. A multi-way comparative analysis was carried out on samples C57/BL HIV gp120 transgenic mice at two, four, eight months age. The results revealed overlapping but distinct populations differential heterogeneity microglia these CNS regions further suggested by disparity plasticity response life span progression HIV-1 pathogenic protein gp120. Our findings indicate adapted local environments fulfill region-specific biological functions.

Язык: Английский

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Viruses and the Brain—A Relationship Prone to Trouble

Viruses, Год журнала: 2025, Номер 17(2), С. 203 - 203

Опубликована: Янв. 31, 2025

Neurological disorders, some of which are associated with viral infections, growing due to the aging and expanding population. Despite strong defenses central nervous system, viruses have evolved ways breach them, often result in dire consequences. In this review, we recount various by different can enter CNS, describe consequences such invasions. Consequences may manifest as acute disease, encephalitis, meningitis, or long-term effects, neuromuscular dysfunction, occurs poliomyelitis. We discuss evidence for involvement causation well-known chronic neurodegenerative diseases, Alzheimer's Parkinson's amyotrophic lateral sclerosis, multiple well vascular dementia elderly. also approaches currently available control a few neural infections. These include antivirals that effective against human immunodeficiency virus herpes simplex virus, vaccines valuable controlling rabies poliomyelitis flavivirus There is an urgent need better understand, at molecular level, how contribute and, especially, neurological diseases develop more precise therapies.

Язык: Английский

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EphB2-mediated ephrin-B reverse signaling on microglia drives an anti-viral, but inflammatory and neurotoxic response associated with HIV

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Background: Pathological inflammation with a loss of synaptic integrity and function has been implicated in HIV Associated Neurocognitive Disorders (HAND). Although therapeutics exist to increase the lifespan people living (PLWH), they are not effective at preventing neuroinflammation induced neuronal damage persists. In this study, we investigate ephrin-B/EphB axis, which regulates inflammation, post-mortem brain specimen PLWH experimental models order assess its potential role neuroinflammation. Methods: We analyze mRNA samples uninfected controls obtained from National NeuroAIDS Tissue Consortium (NNTC) and, for comparison, transgenic mouse model neuroHIV using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Follow-up experiments employ tissue vitro models, including immortalized human microglia, pluripotent stem cell (iPSC)-derived mixed neuroglial cultures, cellular molecular interference, functional multiplex assays, immunofluorescence sequencing examine axis associated neurotoxicity. Results: Using qRT-PCR find increased expression EphB2 PLWH, detect correlation pro-viral DNA, viral RNA an inverse abstract executive verbal fluency. Increased protein level is also observed brains suggesting upregulation can be driven, least part, by gp120 envelope type I interferon, IFNβ. Additionally, induction ephrin-B1 microglia following activation Given previously reported impact on periphery, EphB2-mediated ephrin-B signaling assessed pro-inflammatory anti-viral signature. that treated secrete inflammatory factors but exert contact-independent Finally, knockdown microglial ephrin-B1, binding partner, shows partial alleviation signature Conclusion: Our study suggests elevated EphB2, through contribute neurotoxicity neuroHIV.

Язык: Английский

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Neuroinflammation in HIV-Related Neuropathic Pain

Frontiers in Pharmacology, Год журнала: 2021, Номер 12

Опубликована: Апрель 20, 2021

In the management of human immunodeficiency virus (HIV) infection around world, chronic complications are becoming a new problem along with prolonged life expectancy. Chronic pain is widespread in HIV infected patients and even affects those low viral load undergoing long-term treatment antiviral drugs, negatively influencing adherence to disease quality life. A large proportion neuropathic pain, which defined as caused by nervous system lesions or diseases, presenting series symptoms including both positive negative signs. Injury protein, central peripheral sensitization, side effects antiretroviral therapy lead neuroinflammation, regarded maladaptive mechanism originally serving promote regeneration healing, constituting main HIV-related pain. Gp120, envelope has been found be major toxin that induces Particularly, microglia, releasing numerous pro-inflammatory substances (such TNFα, IL-1β, IL-6), not only sensitize neurons but also center part crosstalk bridging astrocytes oligodendrocytes together forming sensitization during infection, discussed detailly recent reviews. meantime, some NRTIs PIs exacerbate neuroinflammation response. this review, we highlight importance clarifying discuss about limitation related studies future research directions.

Язык: Английский

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HIV-Associated Neurocognitive Disorder: A Look into Cellular and Molecular Pathology

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4697 - 4697

Опубликована: Апрель 25, 2024

Despite combined antiretroviral therapy (cART) limiting HIV replication to undetectable levels in the blood, people living with continue experience HIV-associated neurocognitive disorder (HAND). HAND is associated impairment, including motor and memory loss. has been detected brain within 8 days of estimated exposure mechanisms for this early entry are being actively studied. Once having entered into central nervous system (CNS), degrades blood-brain barrier through production its gp120 Tat proteins. These proteins directly toxic endothelial cells neurons, propagate inflammatory cytokines by activation immune dysregulation tight junction The BBB breakdown progression disease. One main hurdles treatment latent pool cells, which insensitive cART prolong inflammation harboring provirus long-lived that can reactivate, causing damage. Multiple strategies studied combat HAND; however, clinically, these approaches have insufficient require further revisions. goal paper aggregate known challenges HAND.

Язык: Английский

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