Browsing by Subject "microglia"

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  • Kartalou, Georgia-Ioanna; Salgueiro-Pereira, Ana Rita; Endres, Thomas; Lesnikova, Angelina; Casarotto, Plinio; Pousinha, Paula; Delanoe, Kevin; Edelmann, Elke; Castren, Eero; Gottmann, Kurt; Marie, Helene; Lessmann, Volkmar (2020)
    Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms, while a pharmacological treatment that can reverse synaptic and memory deficits in AD mice was thus far not identified. Repurposing food and drug administration (FDA)-approved drugs for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. The sphingosine-1 phosphate analog fingolimod (FTY720) was approved recently for treatment of multiple sclerosis patients. Here, we addressed whether fingolimod rescues AD-related synaptic deficits and memory dysfunction in an amyloid precursor protein/presenilin-1 (APP/PS1) AD mouse model when medication starts after onset of symptoms (at five months). Male mice received intraperitoneal injections of fingolimod for one to two months starting at five to six months. This treatment rescued spine density as well as long-term potentiation in hippocampal cornu ammonis-1 (CA1) pyramidal neurons, that were both impaired in untreated APP/PS1 animals at six to seven months of age. Immunohistochemical analysis with markers of microgliosis (ionized calcium-binding adapter molecule 1; Iba1) and astrogliosis (glial fibrillary acid protein; GFAP) revealed that our fingolimod treatment regime strongly down regulated neuroinflammation in the hippocampus and neocortex of this AD model. These effects were accompanied by a moderate reduction of A beta accumulation in hippocampus and neocortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology that is believed to underlie memory deficits in AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.
  • Choo, Xin Yi; Liddell, Jeffrey R.; Huuskonen, Mikko T.; Grubman, Alexandra; Moujalled, Diane; Roberts, Jessica; Kysenius, Kai; Patten, Lauren; Quek, Hazel; Oikari, Lotta E.; Duncan, Clare; James, Simon A.; McInnes, Lachlan E.; Hayne, David J.; Donnelly, Paul S.; Pollari, Eveliina; Vähätalo, Suvi; Lejavova, Katarina; Kettunen, Mikko; Malm, Tarja; Koistinaho, Jari; White, Anthony R.; Kanninen, Katja M. (2018)
    Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex Cu-II(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of Cu-II(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). Cu-II(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of Cu-II(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.
  • Jokinen, Viljami; Sidorova, Yulia; Viisanen, Hanna; Suleymanova, Ilida; Tiilikainen, Henna; Li, Zhilin; Lilius, Tuomas O.; Matlik, Kert; Anttila, Jenni E.; Airavaara, Mikko; Tian, Li; Rauhala, Pekka V.; Kalso, Eija A. (2018)
    Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal-and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns. Flow cytometry demonstrated that morphine treatment increased the proportion of M2-polarized spinal microglia, but failed to impact the number or the proportion of M1-polarized microglia. In the transcriptome of microglial cells isolated from the spinal cord (SC), morphine treatment increased transcripts related to cell activation and defense response. In the studied brain regions, no activation of microglia or astrocytes was detected by immunohistochemistry, except for a decrease in the number of microglial cells in the substantia nigra. In flow cytometry, morphine caused a decrease in the number of microglial cells in the medulla, but otherwise no change was detected for the count or the proportion of M1-and M2-polarized microglia in the medulla or sensory cortex. No evidence for the activation of glia in the brain was seen. Our results suggest that glial activation associated with opioid tolerance and opioid-induced hyperalgesia occurs mainly at the spinal level. The transcriptome data suggest that the microglial activation pattern after chronic morphine treatment has similarities with that of neuropathic pain. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.
  • Larbalestier, Hannah; Keatinge, Marcus; Watson, Lisa; White, Emma; Gowda, Siri; Wei, Wenbin; Koler, Katjusa; Semenova, Svetlana A.; Elkin, Adam M.; Rimmer, Neal; Sweeney, Sean T.; Mazzolini, Julie; Sieger, Dirk; Hide, Winston; McDearmid, Jonathan; Panula, Pertti; MacDonald, Ryan B.; Bandmann, Oliver (2022)
    The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1(-/- )mutant (gch1(-/-), using CRISPR/Cas technology. gch1(-/-) zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment of gchl(-/-) larvae improved survival without ameliorating the motor phenotype. RNAseq of gchl(-/-) larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation in gchl(-/-). The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.
  • Sun, Weilun; Suzuki, Kunimichi; Toptunov, Dmytro; Stoyanov, Stoyan; Yuzaki, Michisuke; Khiroug, Leonard; Dilyatev, Alexander (2019)
    Two-photon imaging of fluorescently labeled microglia in vivo provides a direct approach to measure motility of microglial processes as a readout of microglial function that is crucial in the context of neurodegenerative diseases, as well as to understand the neuroinflammatory response to implanted substrates and brain-computer interfaces. In this longitudinal study, we quantified surveilling and photodamage-directed microglial processes motility in both acute and chronic cranial window preparations and compared the motility under isoflurane and ketamine anesthesia to an awake condition in the same animal. The isoflurane anesthesia increased the length of surveilling microglial processes in both acute and chronic preparations, while ketamine increased the number of microglial branches in acute preparation only. In chronic (but not acute) preparation, the extension of microglial processes toward the laser-ablated microglial cell was faster under isoflurane (but not ketamine) anesthesia than in awake mice, indicating distinct effects of anesthetics and of preparation type. These data reveal potentiating effects of isoflurane on microglial response to damage, and provide a framework for comparison and optimal selection of experimental conditions for quantitative analysis of microglial function using two-photon microscopy in vivo.
  • Rolova, Taisia; Lehtonen, Sarka; Goldsteins, Gundars; Kettunen, Pinja; Koistinaho, Jari (2021)
    The research on neurodegenerative disorders has long focused on neuronal pathology and used transgenic mice as disease models. However, our understanding of the chronic neurodegenerative process in the human brain is still very limited. It is increasingly recognized that neuronal loss is not caused solely by intrinsic degenerative processes but rather via impaired interactions with surrounding glia and other brain cells. Dysfunctional astrocytes do not provide sufficient nutrients and antioxidants to the neurons, while dysfunctional microglia cannot efficiently clear pathogens and cell debris from extracellular space, thus resulting in chronic inflammatory processes in the brain. Importantly, human glia, especially the astrocytes, differ significantly in morphology and function from their mouse counterparts, and therefore more human-based disease models are needed. Recent advances in stem cell technology make it possible to reprogram human patients' somatic cells to induced pluripotent stem cells (iPSC) and differentiate them further into patient-specific glia and neurons, thus providing a virtually unlimited source of human brain cells. This review summarizes the recent studies using iPSC-derived glial models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discusses the applicability of these models to drug testing. This line of research has shown that targeting glial metabolism can improve the survival and function of cocultured neurons and thus provide a basis for future neuroprotective treatments.
  • Fagerlund, Ilkka; Dougalis, Antonios; Shakirzyanova, Anastasia; Gomez-Budia, Mireia; Pelkonen, Anssi; Konttinen, Henna; Ohtonen, Sohvi; Fazaludeen, Mohammad Feroze; Koskuvi, Marja; Kuusisto, Johanna; Hernandez, Damian; Pebay, Alice; Koistinaho, Jari; Rauramaa, Tuomas; Lehtonen, Sarka; Korhonen, Paula; Malm, Tarja (2022)
    Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of the cerebral cortex. However, a key player in the developing brain, the microglia, do not natively emerge in cerebral organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated from induced pluripotent stem cells, migrate to cerebral organoids, and mature into microglia-like cells and interact with synaptic material. Patch-clamp electrophysiological recordings show that the microglia-like population supported the emergence of more mature and diversified neuronal phenotypes displaying repetitive firing of action potentials, low-threshold spikes and synaptic activity, while multielectrode array recordings revealed spontaneous bursting activity and increased power of gamma-band oscillations upon pharmacological challenge with NMDA. To conclude, microglia-like cells within the organoids promote neuronal and network maturation and recapitulate some aspects of microglia-neuron co-development in vivo, indicating that cerebral organoids could be a useful biorealistic human in vitro platform for studying microglia-neuron interactions.
  • Sierra-Torre, Virginia; Plaza-Zabala, Ainhoa; Bonifazi, Paolo; Abiega, Oihane; Diaz-Aparicio, Irune; Tegelberg, Saara; Lehesjoki, Anna-Elina; Valero, Jorge; Sierra, Amanda (2020)
    Objective Microglial phagocytosis of apoptotic cells is an essential component of the brain regenerative response during neurodegeneration. Whereas it is very efficient in physiological conditions, it is impaired in mouse and human mesial temporal lobe epilepsy, and now we extend our studies to a model of progressive myoclonus epilepsy type 1 in mice lacking cystatin B (CSTB). Methods We used confocal imaging and stereology-based quantification of apoptosis and phagocytosis of the hippocampus ofCstbknockout (KO) mice, an in vitro model of phagocytosis and siRNAs to acutely reduceCstbexpression, and a virtual three-dimensional (3D) model to analyze the physical relationship between apoptosis, phagocytosis, and active hippocampal neurons. Results Microglial phagocytosis was impaired in the hippocampus ofCstbKO mice at 1 month of age, when seizures arise and hippocampal atrophy begins. This impairment was not related to the lack of Cstb in microglia alone, as shown by in vitro experiments with microglial Cstb depletion. The phagocytosis impairment was also unrelated to seizures, as it was also present inCstbKO mice at postnatal day 14, before seizures begin. Importantly, phagocytosis impairment was restricted to the granule cell layer and spared the subgranular zone, where there are no active neurons. Furthermore, apoptotic cells (both phagocytosed and not phagocytosed) inCstb-deficient mice were at close proximity to active cFos(+)neurons, and a virtual 3D model demonstrated that the physical relationship between apoptotic cells and cFos(+)neurons was specific forCstbKO mice. Significance These results suggest a complex crosstalk between apoptosis, phagocytosis, and neuronal activity, hinting that local neuronal activity could be related to phagocytosis dysfunction inCstbKO mice. Overall, these data suggest that phagocytosis impairment is an early feature of hippocampal damage in epilepsy and opens novel therapeutic approaches for epileptic patients based on targeting microglial phagocytosis.
  • Pöyhönen, Suvi (Helsingfors universitet, 2017)
    Cortical stroke induces a chain of events that results in secondary injury in the ipsilateral thalamus. Inflammation is a key player in the delayed injury. Microglia, the resident innate immune cells of the brain, seem to have an important role in the initiation and maintenance of the inflammation. After infarct they are rapidly activated and start to proliferate and release proinflammatory cytokines. They may even phagocytose viable neurons, a phenomenon called "phagoptosis". Many studies, which have aimed at inhibition of the the detrimental function of microglia, suggest that inhibition of microglia might offer promising therapeutical targets. However, microglia are also involved in the resolution and the repair phase after infarct, which makes development of novel therapies challenging. The only approved treatment for ischemic stroke, a fibrinolytic agent, has a very narrow therapeutic time window. Thus, new treatments are urgently needed. Modulation of inflammation may offer a wider therapeutic time window. In this study, we investigated the effects of two potentially neurotrophic factors, CDNF (cerebral dopamine neurotrophic factor) and MANF (mesencephalic astrocyte-derived neurotrophic factor), as well as a specific vitronectin receptor blocker, cRGDfV, on the prevention of neuronal death in thalamus in a transient murine cortical stroke model. MANF and CDNF are proteins released during stress of the endoplasmic reticulum (ER). They have been shown to protect neurons during ER stress and to reduce the production of some proinflammatory mediators. The vitronectin receptor blocker has in vitro inhibited microglial phagoptosis. The treatments were administered as single injections to the thalamus 7 days after the stroke onset. CDNF and MANF alleviated functional deficits, but did not protect thalamic neurons from death or affect the accumulation of phagocytic microglia. cRGDfV neither enhanced functional outcome nor protected neurons from death. The mechanisms of action were not investigated. In addition, we investigated, whether the death of thalamic neurons in the cortical stroke results in sensitization to pain. Central post-stroke pain has been reported on stroke patients and it has been associated with the death or the disturbances in the function of thalamic neurons. However, in spite of significant reduction in the number of neurons in the ipsilateral thalamus and the increase in the accumulation of phagocytic microglia on day 30 after stroke, we did not observe any significant sensitization to pain caused by thermal or mechanical stimuli on days 3, 14 and 28 after stroke. In conclusion, transient ischemic cortical stroke doesn't seem to induce sensitization to pain. MANF and CDNF seem to alleviate functional deficiencies, but they do not protect thalamic neurons from delayed death.
  • Järvinen, Elli Katariina (Helsingin yliopisto, 2021)
    Ischemic stroke is a complex disease involving multiple pathophysiological mechanisms. To date, many therapeutic intervention strategies such as anti-inflammatory treatments have been tested, but none of them has been successful. Previous studies have shown that mesencephalic astrocyte-derived neurotrophic factor (MANF) improves stroke recovery and increases the expression of phagocytosis related genes. In this study, the phagocytic and inflammatory effect of monocyte chemoattractant protein 1 (MCP-1), macrophage colony-stimulating factor (M-CSF), complement component 3 (C3), adhesion G protein-coupled receptor E1 (ADGRE1), MER receptor tyrosine kinase (MerTK) and mesencephalic astrocyte-derived neurotrophic factor (MANF) on microglia were studied simultaneously for the first time. The phagocytosis related genes were transiently transfected into a microglial cell line and studied in vitro utilizing phagocytosis assay, fluorescence-activated cell sorting, Western blot and enzyme-linked immunosorbent assay. MCP-1, M-CSF and C3a were shown to enhance microglial phagocytosis without inducing a pro-inflammatory response. In addition, MerTK induces phagocytosis and the synthesis of pro-inflammatory cytokines. In conclusion, the real therapeutic potential of MCP-1, M-CSF, C3a and MerTK in stroke treatment should be further characterized and tested in vivo.
  • Paetau, Sonja; Rolova, Taisia; Ning, Lin; Gahmberg, Carl G. (2017)
    The intercellular adhesion molecule-5 (ICAM-5) regulates neurite outgrowth and synaptic maturation. ICAM-5 overexpression in the hippocampal neurons induces filopodia formation in vitro. Since microglia are known to prune supernumerous synapses during development, we characterized the regulatory effect of ICAM-5 on microglia. ICAM-5 was released as a soluble protein from N-methyl-D-aspartic acid (NMDA)-treated neurons and bound by microglia. ICAM-5 promoted down-regulation of adhesion and phagocytosis in vitro. Microglia formed large cell clusters on ICAM-5-coated surfaces whereas they adhered and spread on the related molecule ICAM-1. ICAM-5 further reduced the secretion of the proinflammatory cytokines tumor necrosis factor a (TNF-alpha) and interleukin 1 beta (IL-1 beta), but on the contrary induced the secretion of the antiinflammatory IL-10 from lipopolysaccharide (LPS) stimulated microglia. Thus, ICAM-5 might be involved in the regulation of microglia in both health and disease, playing an important neuroprotective role when the brain is under immune challenges and as a "don't-eat-me" signal when it is solubilized from active synapses.
  • Kolosowska, Natalia; Keuters, Meike H.; Wojciechowski, Sara; Keksa-Goldsteine, Velta; Laine, Mika; Malm, Tarja; Goldsteins, Gundars; Koistinaho, Jari; Dhungana, Hiramani (2019)
    Neuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 immediately after the ischemic insult significantly reduced the lesion volume, alleviated the infiltration of CD45(+) leukocytes, and promoted the microglia/macrophage alternative activation within the ischemic region, as determined by arginase 1 (Arg1) immunoreactivity at 3 days post-ischemia (dpi). Moreover, IL-13 enhanced the expression of M2a alternative activation markers Arg1 and Ym1 in the peri-ischemic (PI) area, as well as increased plasma IL-6 and IL-10 levels at 3 dpi. Furthermore, IL-13 treatment ameliorated gait disturbances at day 7 and 14 and sensorimotor deficits at day 14 post-ischemia, as analyzed by the CatWalk gait analysis system and adhesive removal test, respectively. Finally, IL-13 treatment decreased neuronal cell death in a coculture model of neuroinflammation with RAW 264.7 macrophages. Taken together, delivery of IL-13 enhances microglial/macrophage anti-inflammatory responses in vivo and in vitro, decreases ischemia-induced brain cell death, and improves sensory and motor functions in the pMCAo mouse model of cerebral ischemia.
  • Konttinen, Henna; Cabral-da-Silva, Mauricio e Castro; Ohtonen, Sohvi; Wojciechowski, Sara; Shakirzyanova, Anastasia; Caligola, Simone; Giugno, Rosalba; Ishchenko, Yevheniia; Hernández, Damián; Fazaludeen, Mohammad Feroze; Eamen, Shaila; Budia, Mireia Gómez; Fagerlund, Ilkka; Scoyni, Flavia; Korhonen, Paula; Huber, Nadine; Haapasalo, Annakaisa; Hewitt, Alex W.; Vickers, James; Smith, Grady C.; Oksanen, Minna; Graff, Caroline; Kanninen, Katja M.; Lehtonen, Sarka; Propson, Nicholas; Schwartz, Michael P.; Pébay, Alice; Koistinaho, Jari; Ooi, Lezanne; Malm, Tarja (2019)
    Summary Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
  • Nadjar, Agnes; Wigren, Henna-Kaisa M.; Tremblay, Marie-Eve (2017)
    Sleep serves crucial learning and memory functions in both nervous and immune systems. Microglia are brain immune cells that actively maintain health through their crucial physiological roles exerted across the lifespan, including phagocytosis of cellular debris and orchestration of neuroinflammation. The past decade has witnessed an explosive growth of microglial research. Considering the recent developments in the field of microglia and sleep, we examine their possible impact on various pathological conditions associated with a gain, disruption, or loss of sleep in this focused mini-review. While there are extensive studies of microglial implication in a variety of neuropsychiatric and neurodegenerative diseases, less is known regarding their roles in sleep disorders. It is timely to stimulate new research in this emergent and rapidly growing field of investigation.
  • Lahtinen, Lilja (Helsingin yliopisto, 2022)
    Microglia, the resident immune cells of the central nervous system, react to inflammatory stimuli in the brain in a variety of ways. These include migrating to the site of damage and releasing pro- and anti-inflammatory factors. Previous research indicates that these microglial functions require extensive intracellular calcium signaling. Microglial overactivation can exacerbate neuronal damage, especially in cases of chronic inflammation. The ability to modulate the microglial response to damage would therefore be of great clinical relevance. The endoplasmic reticulum (ER) acts as the cell’s main calcium store and regulates cellular calcium levels primarily through the activity of ryanodine receptors (RYR), inositol-triphosphate receptors (IP3R), and the sarco-endoplasmic reticulum calcium ATPase (SERCA) pump. Calcium depletion from the ER is associated with cellular stress and microglial reactivity and therefore the ER may be an important target for modulating the microglial reactive response. The aim of this study is to show whether ER calcium depletion in a microglial cell line causes changes in protein expression, cellular infiltration, and the release of key pro-inflammatory factors. Drugs that block the pumping of calcium from the cytosol via the SERCA pump, such as thapsigargin, effectively induce a state of calcium depletion in the ER. In the present study, treatment with the SERCA pump inhibitor thapsigargin was found to increase SERCA2 expression in BV2, but not SV40, microglial cell lines. Treatment of microglia with thapsigargin was associated with large increases in the release of pro-inflammatory factors IL-6 and TNF-alpha but had no effect on microglial migration.
  • Tallberg, Robert Georg Michael (Helsingin yliopisto, 2021)
    The immune system is crucial in the central nervous system (CNS), protecting sensitive tissues, promoting regeneration, and maintaining homeostasis. It is involved in CNS-disorders, such as neurodegenerative diseases and neurological insults related to stroke. Critical myeloid leukocytes in the CNS are microglia, divided into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. This polarization achieves modulation of the inflammatory response by amplifying or dampening it. Therefore, microglia are widely investigated in CNS-disorders. β2-integrins are adhesion proteins that mediate inflammation. They are expressed explicitly on leukocytes, including microglia. Important processes, such as phagocytosis and cell motility, are regulated by β2-integrins. They also relay downstream signals, altering inflammation in many settings, although their effects on microglial properties and stroke are currently poorly understood. We here aimed to investigate the role of β2-integrins in stroke-related injury and microglia polarization in vivo using knock-in (KI) mice, which lack functional β2-integrins. Our results show that in a mouse model of haemorrhagic stroke, the functional outcome was less severe in β2-integrin KI versus wild-type (WT) mice (P = 0.0147), suggesting that β2-integrins are involved in stroke pathophysiology. Furthermore, by using flow cytometry we observed significantly lower frequencies of M1 microglia in the KI mouse brain (P = 0.0096). Therefore, our findings reveal neuroprotective aspects by inhibiting β2-integrins in neuroinflammation. Investigating microglial properties mediated by β2-integrins could contribute to the understanding of neuroinflammatory events, leading to the development of therapies for poorly treated CNS-disorders. Our results suggest that β2-integrins should be further explored as molecular targets for novel stroke treatments.
  • Albert, Katrina; Niskanen, Jonna; Kälvälä, Sara; Lehtonen, Šárka (2021)
    Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.