Microglia
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Zápalový proces je nevyhnutnou odpoveďou na poškodenie rôzneho pôvodu, ktorý sa odohráva aj v centrálnom nervovom systéme (CNS). Hoci hromadiace sa údaje presvedčivo dokumentujú, že chronický zápalový proces je dôležitou súčasťou neurodegenratívnych chorôb, akými sú Alzheimerova choroba, Parkinsonova choroba, Huntingtonova choroba, menej je známe o akútnom zápalovom procese v CNS. Zatiaľ čo neurodegeneratívne choroby sú charakterizované neprítomnosťou významnej infiltrácie z krvi pochádzajúcich mononukleárnych buniek, prítomnosť mikroglie/makrofágov je typická pre akútnu neuroinflamáciu. V priebehu fokálnej, netraumatickej neuroinflamácie, ktorá je vyvolaná mikroinjekciou zymosanu do parenchýmu miechy, dochádza k miestnej aktivizácii mikroglie/makrofágov. V našej práci sme zisťovali vznik, rozsah a vývoj fokálnej lézie a priebeh aktivizácie mikroglie/makrofágov po stereotaxickej aplikácii zymosanu (100 nl) do bočných povrazcov miechy v akútnom období po podaní zymosanu (6 hod.–8 dní). Intenzívnu aktivitu NADPH-diaforázy v makrofágoch lézie sme sledovali 1–4 dni po zymosanovej injekcii, v ďalsích dňoch prežívania klesala. Naše výsledky potvrdzujú aktívnu úlohu mikroglie/makrofágov pri fokálnej netraumatickej neuroinflamácii a podporujú inovatívne názory na procesy akútnej neuroinflamácie v CNS.
Inflammation is an inevitable response on injury of different origin that takes place, as well, in the central nervous system (CNS). Although accumulating evidence suggests that chronic inflammation plays an important part in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, less is known about the processes of the acute CNS inflammation. While neurodegenerative diseases are characterized by the lack of the prominent infiltrates of blood-derived mononuclear cells the involvement of microglia/macrophages is typical for the acute neuroinflammation. Focal non-traumatic neuroinflammation produced by microinjection of zymosan to the parenchyma of spinal cord induces local activation of microglia/macrophages. In our study, we evaluated focal lesion progress and microglia/macrophages response following stereotaxic application of zymosan (100 nl) to the lateral funiculi of the spinal cord in acute post-injection time period (6 h–8 days). Intensive expression of NADPH-diaphorase in lesion macrophages was observed 1–4 days after zymosan injection, in the next days its activity declined. Our results confirm active role of microglia/macrophages in focal non-traumatic neuroinflammation and strengthen innovative view on processes of acute inflammation in CNS.
- MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus MeSH
- makrofágy enzymologie MeSH
- mícha enzymologie patologie MeSH
- mikroglie imunologie MeSH
- modely u zvířat MeSH
- NADPH-dehydrogenasa analýza MeSH
- neurogenní zánět imunologie patologie MeSH
- zvířata MeSH
- zymosan aplikace a dávkování MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
Pain and pain modulation has been viewed as being mediated solely by neurons. However, new research implicates spinal cord glia (microglia and astrocytes) as key players in the creation and maintenance of pathological pain. Sciatic nerve lesions are one of the most commonly studied pain-related injuries. In our study we aimed to characterize changes in microglia activation after axotomy and chronic constriction injury of the sciatic nerve of rats in the spinal cord and dorsal root ganglia (DRG) as well as to evaluate this activation in regard to pain behaviour in injured and sham groups of rats. Microglial activation was observed at the ipsilateral side of lumbar spinal cord as well as at L4–L6 DRG in all experimental groups. There were slight differences in the level and extent of microglia activation between nerve injury models used, however, differences were clear between nerve-injured and sham animals in accordance with different level of pain behaviour in these groups. It is known that activated microglia release various chemical mediators that can alter the function of neurons. Robust microglial activation observed in present study could contribute to pathological pain states observed following nerve injury. As neuropathic pain is by large not relieved by current therapies that target neurons, it is suggested that targeting glia might provide a novel approach for treatment of such unremitting pain conditions.
Microglia play key immunological roles in the central nervous system. Upon activation, resident microglial cells transform from a ramified form to an amoeboid form and acquire the ability to phagocytose and release pro-inflammatory cytokines. Here, we review microglial phenotypes that contribute to their functional roles in the central nervous system with the emphasis on their molecular profiles. Deeper understanding of the functions performed by microglia in physiological and pathological conditions can promote investigation of microglia activities in brain injury or disease and facilitate development of new treatment approaches.
Activation of microglia in the spinal cord dorsal horn after peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that after peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.
- MeSH
- bolest * patologie patofyziologie MeSH
- extracelulární matrix patologie MeSH
- hyperalgezie * etiologie patologie patofyziologie MeSH
- krysa rodu rattus MeSH
- mikroglie * patologie MeSH
- poranění periferního nervu * komplikace patologie MeSH
- potkani Sprague-Dawley MeSH
- zadní rohy míšní * patologie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The activity of the immune system is controlled by circadian clocks present in different immune cells. The brain-resident subtype of immune cells, microglia, exhibits a wide range of functional phenotypes depending on the signaling molecules in their microenvironment. The exact role of microglia in the hypothalamic suprachiasmatic nuclei (SCN), the central circadian clock, has not been known. Therefore, the aim of this study was to determine (1) whether microenvironment-induced changes in microglial polarization affect circadian clocks in these cells and (2) whether the presence of microglia contributes to SCN clock function. Microglial and SCN clocks were monitored using PER2-driven bioluminescence rhythms at the tissue and single-cell levels. We found that polarization of resting microglia to a pro-inflammatory (M1) or anti-inflammatory (M2) state significantly altered the period and amplitude of their molecular circadian clock; importantly, the parameters changed plastically with the repolarization of microglia. This effect was reflected in specific modulations of the expression profiles of individual clock genes in the polarized microglia. Depletion of microglia significantly reduced the amplitude of the SCN clock, and co-cultivation of the SCN explants with M2-polarized microglia specifically improved the amplitude of the SCN clock. These results demonstrate that the presence of M2-polarized microglia has beneficial effects on SCN clock function. Our results provide new insight into the mutual interaction between immune and circadian systems in the brain.
- MeSH
- cirkadiánní hodiny * genetika MeSH
- cirkadiánní rytmus fyziologie MeSH
- mikroglie MeSH
- mozek MeSH
- myši MeSH
- nucleus suprachiasmaticus metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- buněčná diferenciace MeSH
- histocytochemie metody MeSH
- krysa rodu rattus MeSH
- mikroglie anatomie a histologie cytologie chemie MeSH
- mikroskopie MeSH
- potkani Wistar anatomie a histologie embryologie růst a vývoj MeSH
- telencefalon anatomie a histologie chemie MeSH
- vývoj plodu MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- kongresy MeSH
- srovnávací studie MeSH
Current critical thinking has displaced the elaborated beta amyloid theory as the underlying unitary mechanism of Alzheimer disease (AD) in favor of concerted, long-term disruption or dysregulation of broad-based physiological processes. We present a critical discussion in which a chronic state of systemic proinflammation sustained over the course of several decades and engendered by ongoing metabolic or autoimmune disease is predicted to promote severe disruptions of central neurological processes. Specifically, long-term functional rundown of microglial-mediated phagocytic activity in concert with aberrant expression and cellular deposition of beta amyloid and tau protein facilitates formation of senile plaques and neurofibrillary tangles. Within this functional context, we hypothesize that early initiation events in the pathophysiology of AD may operationally involve a convergence of dysregulated peripheral and central constitutive nitric oxide signaling pathways resulting from a chronic state of systemic proinflammation and leading to severely dysfunctional "hyperactivated" microglia.
- MeSH
- Alzheimerova nemoc * metabolismus patologie patofyziologie MeSH
- lidé MeSH
- mikroglie * metabolismus patologie MeSH
- oxid dusnatý metabolismus MeSH
- signální transdukce * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodníky MeSH
Berberine (BBR), a small molecule protoberberine isoquinoline alkaloid, is easy to cross the blood-brain barrier and is a potential drug for neurodegenerative diseases. Here, we explored the role and molecular mechanism of BBR in Alzheimer's disease (AD) progression. Weighted gene co-expression network analysis (WGCNA) was conducted to determine AD pathology-associated gene modules and differentially expressed genes (DEGs) were also identified. GO and KEGG analyses were performed for gene function and signaling pathway annotation. Cell counting kit-8 (CCK8) assay was applied to analyze cell viability. Immunofluorescence (IF) staining assay was conducted to measure the levels of polarization markers. The production of inflammatory cytokines was analyzed by enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) level and mitochondrial membrane potential (MMP) were detected using a ROS detection kit and a MMP Detection Kit (JC-1), respectively. AD pathology-associated DEGs were applied for GO function annotation and KEGG enrichment analysis, and the results uncovered that AD pathology was related to immune and inflammation. Lipopolysaccharide (LPS) exposure induced the M1 phenotype of microglia, and BBR suppressed LPS-induced M1 polarization and induced microglia toward M2 polarization. Through co-culture of microglia and neuronal cells, we found that BBR exerted a neuro-protective role by attenuating the injury of LPS-induced HMC3 on SH-SY5Y cells. Mechanically, BBR switched the M1/M2 phenotypes of microglia by activating PI3K-AKT signaling. In summary, BBR protected neuronal cells from activated microglia-mediated neuro-inflammation by switching the M1/M2 polarization in LPS-induced microglia via activating PI3K-AKT signaling. Key words Alzheimer's Disease, Berberine, Microglia polarization, Neuroinflammation, PI3K-AKT signaling.
- MeSH
- Alzheimerova nemoc * metabolismus farmakoterapie patologie MeSH
- berberin * farmakologie terapeutické užití MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- lidé MeSH
- mikroglie * účinky léků metabolismus MeSH
- myši MeSH
- neuroprotektivní látky * farmakologie MeSH
- polarita buněk účinky léků MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- signální transdukce * účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
