Activation of Swell1 in microglia suppresses neuroinflammation and reduces brain damage in ischemic stroke

Chen, Baoyi; Xie, Cong; Shi, Tengrui; Yue, Shiqin; Li, Weiping; Huang, Guodong; Zhang, Yuan; Liu, Wenlan

doi:10.1016/j.nbd.2022.105936

Cited by 7 publications

(6 citation statements)

References 57 publications

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“…In rats assessed 2–4 weeks after ischemic injury, minocycline improved perfusion, reduced BBB permeability with higher levels of TJ proteins, and decreased the frequency of proinflammatory microglia, shifting their activation to an M2-like, or anti-inflammatory, phenotype with upregulation of transforming growth factor beta (TGF- β) and IL-10 and decreased TNF-α and IL-1β ( Yang et al, 2015 ). Additionally, a transient MCAO CX3cr1-Cre mouse model with conditional knock-in overexpression of the chloride transmembrane transporter, Swell1, resulted in anti-inflammatory microglial activation and reduced brain injury ( Chen et al, 2023 ). Brain and serum from Cre-Swell1 mice had lower levels of pro-inflammatory factors IL-1β, IL-6, macrophage inflammatory protein (MIP) 1β, TNF-α, and IFN-γ and increased levels of anti-inflammatory, IL-4 and IL-10, as compared to control animals ( Chen et al, 2023 ).…”

Section: Strokementioning

confidence: 99%

“…Additionally, a transient MCAO CX3cr1-Cre mouse model with conditional knock-in overexpression of the chloride transmembrane transporter, Swell1, resulted in anti-inflammatory microglial activation and reduced brain injury ( Chen et al, 2023 ). Brain and serum from Cre-Swell1 mice had lower levels of pro-inflammatory factors IL-1β, IL-6, macrophage inflammatory protein (MIP) 1β, TNF-α, and IFN-γ and increased levels of anti-inflammatory, IL-4 and IL-10, as compared to control animals ( Chen et al, 2023 ). Further exploration demonstrated that Swell1 overexpression in a mouse microglial cell line, BV2 cells, cultured in a hypotonic environment to activate chlorine channels, activated cAMP response element-binding protein (CREB) and forkhead box O3 (FOXO3a) transcription factors and the negative regulator of the NLRP3 inflammasome, WNK lysine deficient protein kinase 1 (WNK1) ( Chen et al, 2023 ).…”

Section: Strokementioning

confidence: 99%

“…Brain and serum from Cre-Swell1 mice had lower levels of pro-inflammatory factors IL-1β, IL-6, macrophage inflammatory protein (MIP) 1β, TNF-α, and IFN-γ and increased levels of anti-inflammatory, IL-4 and IL-10, as compared to control animals ( Chen et al, 2023 ). Further exploration demonstrated that Swell1 overexpression in a mouse microglial cell line, BV2 cells, cultured in a hypotonic environment to activate chlorine channels, activated cAMP response element-binding protein (CREB) and forkhead box O3 (FOXO3a) transcription factors and the negative regulator of the NLRP3 inflammasome, WNK lysine deficient protein kinase 1 (WNK1) ( Chen et al, 2023 ). This study revealed that chlorine sensing signal pathways promte an anti-inflammatory responses by microglia, reducing injury and inflammation after stroke.…”

Section: Strokementioning

confidence: 99%

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Microglia at the blood brain barrier in health and disease

Mayer,

Fischer

2024

Front. Cell. Neurosci.

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The blood brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by selectively preventing the entry of substances from the peripheral blood into the central nervous system (CNS). Comprised of endothelial cells, pericytes, and astrocytes, this highly regulated barrier encompasses the majority of the brain’s vasculature. In addition to its protective function, the BBB also engages in significant crosstalk with perivascular macrophages (MΦ) and microglia, the resident MΦ of the brain. These interactions play a pivotal role in modulating the activation state of cells comprising the BBB, as well as MΦs and microglia, themselves. Alterations in systemic metabolic and inflammatory states can promote endothelial cell dysfunction, reducing the integrity of the BBB and potentially allowing peripheral blood factors to leak into the CNS compartment. This may mediate activation of perivascular MΦs, microglia, and astrocytes, and initiate further immune responses within the brain parenchyma, suggesting neuroinflammation can be triggered by signaling from the periphery, without primary injury or disease originating within the CNS. The intricate interplay between the periphery and the CNS through the BBB highlights the importance of understanding the role of microglia in mediating responses to systemic challenges. Despite recent advancements, our understanding of the interactions between microglia and the BBB is still in its early stages, leaving a significant gap in knowledge. However, emerging research is shedding light on the involvement of microglia at the BBB in various conditions, including systemic infections, diabetes, and ischemic stroke. This review aims to provide a comprehensive overview of the current research investigating the intricate relationship between microglia and the BBB in health and disease. By exploring these connections, we hope to advance our understanding of the role of brain immune responses to systemic challenges and their impact on CNS health and pathology. Uncovering these interactions may hold promise for the development of novel therapeutic strategies for neurological conditions that involve immune and vascular mechanisms.

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Section: Strokementioning

confidence: 99%

Section: Strokementioning

confidence: 99%

Section: Strokementioning

confidence: 99%

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Microglia at the blood brain barrier in health and disease

Mayer,

Fischer

2024

Front. Cell. Neurosci.

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“…13 Microglia, the brain's primary immune responders, exhibit various phenotypes, notably the pro-inflammatory and the antiinflammatory. [14][15][16] The pro-inflammatory phenotype exacerbates neurological deficits post-ICH through harmful cytokine and ROS production. 17,18 Conversely, The anti-inflammatory phenotype helps in post-ICH recovery by producing anti-inflammatory factors and accelerating the removal of tissue debris and cell regeneration.…”

Section: Introductionmentioning

confidence: 99%

“…Microglia, the brain's primary immune responders, exhibit various phenotypes, notably the pro‐inflammatory and the anti‐inflammatory 14–16 . The pro‐inflammatory phenotype exacerbates neurological deficits post‐ICH through harmful cytokine and ROS production 17,18 .…”

Section: Introductionmentioning

confidence: 99%

Attenuation of neuronal ferroptosis in intracerebral hemorrhage by inhibiting HDAC1/2: Microglial heterogenization via the Nrf2/HO1 pathway

Jiang,

Yang,

et al. 2024

CNS Neurosci Ther

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AimThe class I histone deacetylases (HDACs) implicate in microglial heterogenization and neuroinflammation following Intracerebral hemorrhage (ICH). Ferroptosis has also been reported in the ICH model. However, the relationship between HDAC1/2's role in microglial heterogenization and neuronal ferroptosis remains unclear.MethodsIn both in vivo and in vitro models of ICH, we used Romidepsin (FK228), a selective HDAC1/2 inhibitor, to investigate its effects on microglial heterogenization and neuronal ferroptosis. In the in vitro ICH model using Hemin, a transwell system was utilized to examine how microglia‐driven inflammation and ICH‐triggered neuronal ferroptosis interact. Immunostaining, Western blotting and RT‐qPCR were used to evaluate the microglial heterogenization and neuronal ferroptosis. Microglial heterogenization, neuronal ferroptosis, and neurological dysfunctions were assessed in vivo ICH mice model performed by autologous blood injection.ResultsHDAC1/2 inhibition altered microglial heterogenization after ICH, as showing the reducing neuroinflammation and shifting microglia towards an anti‐inflammatory phenotype by immunostaining and qPCR results. HDAC1/2 inhibition reduced ferroptosis, characterized by high ROS and low GPx4 expression in HT22 cells, and reduced iron and lipid deposition post‐ICH in vivo. Additionally, the Nrf2/HO1 signaling pathway, especially acetyl‐Nrf2, activated in the in vivo ICH model due to HDAC1/2 inhibition, plays a role in regulating microglial heterogenization. Furthermore, HDAC1/2 inhibition improved sensorimotor and histological outcomes post‐ICH, offering a potential mechanism against ICH.ConclusionInhibition of HDAC1/2 reduces neuro‐ferroptosis by modifying the heterogeneity of microglia via the Nrf2/HO1 pathway, with a particular focus on acetyl‐Nrf2. Additionally, this inhibition aids in the faster removal of hematomas and lessens prolonged neurological impairments, indicating novel approach for treating ICH.

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