Silencing the Cytoskeleton Protein Iba1 (Ionized Calcium Binding Adapter Protein 1) Interferes with BV2 Microglia Functioning

Gheorghe, Roxana; Deftu, Alexandru‐Florian; Filippi, Alexandru; Grosu, Andreea; Bica-Popi, Melania; Chirițoiu, Marioara; Chirițoiu, Gabriela; Munteanu, Cristian V. A.; Silvestro, Luigi; Ristoiu, Violeta

doi:10.1007/s10571-020-00790-w

Cited by 22 publications

(22 citation statements)

References 67 publications

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“…(Imai and Kohsaka, 2002). Recent study suggest that siRNA based silencing of Iba1 leads to reduced proliferation, cell adhesion whereas increased phagocytic activity of BV2 microglia cells indicating a new microglia target to modulate microglia and its functions (Gheorghe et al, 2020). Natural products are widely used in reducing redox imbalance and inflammation in different organ system including brain.…”

Section: Sulforaphanementioning

confidence: 99%

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

et al. 2021

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Microglia, a type of innate immune cell of the brain, regulates neurogenesis, immunological surveillance, redox imbalance, cognitive and behavioral changes under normal and pathological conditions like Alzheimer’s, Parkinson’s, Multiple sclerosis and traumatic brain injury. Microglia produces a wide variety of cytokines to maintain homeostasis. It also participates in synaptic pruning and regulation of neurons overproduction by phagocytosis of neural precursor cells. The phenotypes of microglia are regulated by the local microenvironment of neurons and astrocytes via interaction with both soluble and membrane-bound mediators. In case of neuron degeneration as observed in acute or chronic neurodegenerative diseases, microglia gets released from the inhibitory effect of neurons and astrocytes, showing activated phenotype either of its dual function. Microglia shows neuroprotective effect by secreting growths factors to heal neurons and clears cell debris through phagocytosis in case of a moderate stimulus. But the same microglia starts releasing pro-inflammatory cytokines like TNF-α, IFN-γ, reactive oxygen species (ROS), and nitric oxide (NO), increasing neuroinflammation and redox imbalance in the brain under chronic signals. Therefore, pharmacological targeting of microglia would be a promising strategy in the regulation of neuroinflammation, redox imbalance and oxidative stress in neurodegenerative diseases. Some studies present potentials of natural products like curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane to suppress activation of microglia. These natural products have also been proposed as effective therapeutics to regulate the progression of neurodegenerative diseases. The present review article intends to explain the molecular mechanisms and functions of microglia and molecular dynamics of microglia specific genes and proteins like Iba1 and Tmem119 in neurodegeneration. The possible interventions by curcumin, resveratrol, cannabidiol, ginsenosides, flavonoids and sulforaphane on microglia specific protein Iba1 suggest possibility of natural products mediated regulation of microglia phenotypes and its functions to control redox imbalance and neuroinflammation in management of Alzheimer’s, Parkinson’s and Multiple Sclerosis for microglia-mediated therapeutics.

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Section: Sulforaphanementioning

confidence: 99%

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

et al. 2021

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“…These different concentrations would differentially regulate microglial [Ca 2+ ] c with the active participation of SERCA2b to alternatively promote molecular pathways responsible for migration or phagocytosis. In this sense, it has been recently reported that BV2 microglia silenced for Iba1, which binds Ca 2+ and acts as actin‐cross linking protein (Sasaki, Ohsawa, Kanazawa, Kohsaka, & Imai, 2001), migrated less, but exhibited increased phagocytic activity (Gheorghe et al, 2020), supporting the important role of Ca 2+ signaling and cytoskeleton dynamics in these microglial functions.…”

Section: Discussionmentioning

confidence: 90%

The endoplasmic reticulum Ca²⁺‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis

Morales-Ropero

Arroyo-Urea

Neubrand

et al. 2020

Glia

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Activation of microglia is an early immune response to damage in the brain. Although a key role for Ca2+ as trigger of microglial activation has been considered, little is known about the molecular scenario for regulating Ca2+ homeostasis in these cells. Taking into account the importance of the endoplasmic reticulum as a cellular Ca2+ store, the sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA2b) is an interesting target to modulate intracellular Ca2+ dynamics. We found upregulation of SERCA2b in activated microglia of human brain with Alzheimer's disease and we further studied the participation of SERCA2b in microglial functions by using the BV2 murine microglial cell line and primary microglia isolated from mouse brain. To trigger microglia activation, we used the bacterial lipopolysaccharide (LPS), which is known to induce an increase of cytosolic Ca2+. Our results showed an upregulated expression of SERCA2b in LPS‐induced activated microglia likely associated to an attempt to restore the increased cytosolic Ca2+ concentration. We analyzed SERCA2b contribution in microglial migration by using the specific SERCA inhibitor thapsigargin in scratch assays. Microglial migration was strongly stimulated with thapsigargin, even more than with LPS‐induction, but delayed in time. However, phagocytic capacity of microglia was blocked in the presence of the SERCA inhibitor, indicating the importance of a tight control of cytosolic Ca2+ in these processes. All together, these results provide for the first time compelling evidence for SERCA2b as a major player regulating microglial functions, affecting migration and phagocytosis in an opposite manner.

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“…However, emerging evidence suggests otherwise [ 71 ]. Recent experiments on the murine microglia BV2 cell line showed that silencing Iba1 protein in microglial cells leads to a significant decrease in cell migration, proliferation, and cell adhesion capabilities [ 72 ]. Further, the authors demonstrated that such silencing leads to an increase in phagocytic activity along with upregulation of P2 × 7 (ATP-activated P2 purinergic receptors) functioning [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recent experiments on the murine microglia BV2 cell line showed that silencing Iba1 protein in microglial cells leads to a significant decrease in cell migration, proliferation, and cell adhesion capabilities [ 72 ]. Further, the authors demonstrated that such silencing leads to an increase in phagocytic activity along with upregulation of P2 × 7 (ATP-activated P2 purinergic receptors) functioning [ 72 ]. This is of immense interest since, in our study, we found that in controls, 45–55% of the entire microglial population in SNpc and 65–70% of the entire microglial population in SNpr did not demonstrate Iba1 expression ( Figure 7 and Figure 8 ).…”

Section: Discussionmentioning

confidence: 99%

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Chronic Alcoholism and HHV-6 Infection Synergistically Promote Neuroinflammatory Microglial Phenotypes in the Substantia Nigra of the Adult Human Brain

et al. 2021

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Both chronic alcoholism and human herpesvirus-6 (HHV-6) infection have been identified as promoters of neuroinflammation and known to cause movement-related disorders. Substantia Nigra (SN), the dopaminergic neuron-rich region of the basal ganglia, is involved in regulating motor function and the reward system. Hence, we hypothesize the presence of possible synergism between alcoholism and HHV-6 infection in the SN region and report a comprehensive quantification and characterization of microglial functions and morphology in postmortem brain tissue from 44 healthy, age-matched alcoholics and chronic alcoholics. A decrease in the perivascular CD68+ microglia in alcoholics was noted in both the gray and white matter. Additionally, the CD68+/Iba1− microglial subpopulation was found to be the dominant type in the controls. Conversely, in alcoholics, dystrophic changes in microglia were seen with a significant increase in Iba1 expression and perivascular to diffuse migration. An increase in CD11b expression was noted in alcoholics, with the Iba1+/CD11b− subtype promoting inflammation. All the controls were found to be negative for HHV-6 whilst the alcoholics demonstrated HHV-6 positivity in both gray and white matter. Amongst HHV-6 positive alcoholics, all the above-mentioned changes were found to be heightened when compared with HHV-6 negative alcoholics, thereby highlighting the compounding relationship between alcoholism and HHV-6 infection that promotes microglia-mediated neuroinflammation.

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Silencing the Cytoskeleton Protein Iba1 (Ionized Calcium Binding Adapter Protein 1) Interferes with BV2 Microglia Functioning

Cited by 22 publications

References 67 publications

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

The endoplasmic reticulum Ca²⁺‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis

Chronic Alcoholism and HHV-6 Infection Synergistically Promote Neuroinflammatory Microglial Phenotypes in the Substantia Nigra of the Adult Human Brain

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Silencing the Cytoskeleton Protein Iba1 (Ionized Calcium Binding Adapter Protein 1) Interferes with BV2 Microglia Functioning

Cited by 22 publications

References 67 publications

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

Microglia Specific Drug Targeting Using Natural Products for the Regulation of Redox Imbalance in Neurodegeneration

The endoplasmic reticulum Ca2+‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis

Chronic Alcoholism and HHV-6 Infection Synergistically Promote Neuroinflammatory Microglial Phenotypes in the Substantia Nigra of the Adult Human Brain

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The endoplasmic reticulum Ca²⁺‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis