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Browsing by Subject "microglia"

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  • Mäkinen, Hilla (2023)
    Morphological features are considered as markers of microglial functionality, and they show regional heterogeneity in the brain. Recently the sleep-wake cycle was shown to affect microglial morphology in mice and correlate with cortical sleep slow wave activity (SWA). Microglial sizes and ramification increased during the dark period and decreased during the light period in cerebral areas associated with SWA, suggesting that neuronal activation could be affecting microglial morphology through SWA. I studied microglia in the hindbrain areas with and without functional connection to SWA to further investigate the association between SWA and alterations in morphology, and to investigate if there are differences in microglial morphology and their diurnal alterations in brain regions other than those commonly investigated. I examined three hindbrain areas (cerebellar cortex (CC), deep cerebellar nucleus (DCN) and medial vestibular nucleus (MVN)) and somatosensory cortex (SC) of mice (n=15) at two timepoints: 6 hours after the light onset (high SWA) and offset (low SWA). My aims were to answer if there are morphological differences in microglia between 1) the four brain areas at both timepoints and 2) between the two timepoints in each brain area. My hypotheses were that CC and DCN which have functional connections to cortical SWA, would show similar diurnal morphology alterations as demonstrated in the cerebral areas, and MVN that has no known cortical SWA connection, would lack significant alterations. As microglia are heterogenous throughout brain, I expected microglia to differ between different brain areas, especially the hindbrain and the SC. I found that microglial morphologies significantly differed between the hindbrain and the cortex, while the hindbrain areas were more similar in morphology. Moreover, the brain areas demonstrated diurnal morphology alterations of microglia with varying extent: CC and DCN microglial morphology did not correlate with SWA as clearly as SC did, and interestingly, morphological features of MVN microglia showed a pattern opposite to other areas, microglia being larger during the light period than the dark period. These results highlight the importance of the diurnal time to microglial morphology and the heterogeneity of microglia between different brain regions.
  • Pihl, Enni-Eveliina (2023)
    Microglia, the resident macrophage-like glial cells of the central nervous system (CNS), form the first line of defense against pathogens in the brain, and regulate both innate and adaptive immunity. Any abnormalities in their microenvironment lead to microglial activation, characterized by alterations in their gene expression, morphology, and functional behavior. Once activated, microglia respond to CNS injury and inflammation by, e.g., migrating to the site of damage, releasing pro-inflammatory cytokines, as well as phagocyting cell debris and pathogens. Prolonged activation of microglia expressing pro-inflammatory phenotypes can lead to exacerbated CNS damage. Hence, limiting CNS inflammation by stimulating microglial polarization towards their pro-resolving phenotypes would be of great clinical relevance. The research of our laboratory focuses on CNS injury and repair, as well as finding novel therapies for ischemic stroke. Specialized pro-resolving mediators (SPMs) derived from essential fatty acids have been proposed to offer a potential therapeutic approach for ischemic stroke via promoting resolution of post-stroke inflammation. Previous studies have revealed the ability of SPMs to induce a transformation of macrophages, the immune cells strongly resembling microglia, towards their anti-inflammatory phenotypes. The aim of this study was therefore to assess whether SPMs have similar effects on BV2 microglia, specifically on their lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). In addition to assessing the cytokine levels, our aim was to determine the optimal conditions for studying the effects of SPMs on microglial migration. In the present study, the levels of TNF-α and IL-6 were determined by specific ELISAs, and the transwell assay was used to measure microglial migration. Resolvins E1 (RvE1) and D1 (RvD1), as well as protectin D1 (PD1) and 15-epimer of lipoxin A4 (15-epi-LXA4) were all associated with decreased levels of TNF-α and IL-6, with RvE1 having the most potential as a resolving agent. In addition, we observed that serum starvation notably decreases the release of IL-6 and affects microglial migration. Overall, our results support the idea that SPMs could provide a novel therapeutic strategy for stroke therapy as they contribute to the resolution of CNS inflammation.
  • Lahtinen, Lilja (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 (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.