Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury

Greenhalgh, Andrew D.; Zarruk, Juan G.; Healy, Luke M.; Jesudasan, Sam Joshva Baskar; Jhelum, Priya; Salmon, Christopher; Formanek, Albert; Russo, Matthew V.; Antel, Jack P.; McGavern, Dorian B.; McColl, Barry W.; David, Samuel

doi:10.1371/journal.pbio.2005264

Cited by 166 publications

(179 citation statements)

References 79 publications

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“…Furthermore, we examined monocyte/macrophage extravasation using CD11b. Consistent with previous reports that CD11b is able to label brain-resident microglia in addition to monocytes/macrophages [63,64], CD11b + cells (microglia) were detected in sham animals (Fig. 6e).…”

Section: Pko Mice Show Enhanced Inflammatory Cell Extravasation Aftersupporting

confidence: 92%

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

Gautam

Nirwane

et al. 2020

J Neuroinflammation

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Background: Mural cells synthesize and deposit laminin to the basement membrane. To investigate the function of mural cell-derived laminin, we generated a mutant mouse line lacking mural cell-derived laminin (termed PKO). In a previous study, we showed that the PKO mice were grossly normal under homeostatic condition, but developed blood-brain barrier (BBB) breakdown with advanced age (> 8 months), suggesting that these mutants are intrinsically weak. Based on these findings, we hypothesized that PKO mice have exacerbated injuries in pathological conditions. Methods: Using collagenase-induced intracerebral hemorrhage (ICH) as an injury model, we examined various stroke outcomes, including hematoma volume, neurological function, neuronal death, BBB integrity, paracellular/ transcellular transport, inflammatory cell infiltration, and brain water content, in PKO mice and their wildtype littermates at young age (6-8 weeks). In addition, transmission electron microscopy (TEM) analysis and an in vitro ICH model were used to investigate the underlying molecular mechanisms. Results: Compared to age-matched wildtype littermates, PKO mice display aggravated stroke outcomes, including larger hematoma size, worse neurological function, increased neuronal cell death, enhanced BBB permeability, increased transcytosis, and elevated inflammatory cell infiltration. These mutants also exhibit high baseline brain water content independent of aquaporin-4 (AQP4). In addition, mural cell-derived laminin significantly reduced caveolin-1 without affecting tight junction proteins in the in vitro ICH model. Conclusions: These results suggest that mural cell-derived laminin attenuates BBB damage in ICH via decreasing caveolin-1 and thus transcytosis, regulates brain water homeostasis, and plays a beneficial role in ICH.

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Section: Pko Mice Show Enhanced Inflammatory Cell Extravasation Aftersupporting

confidence: 92%

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

Gautam

Nirwane

et al. 2020

J Neuroinflammation

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“…The primary injury causes a structural disturbance at the time of injury [3]. Then, a long-term secondary injury is considered a complicated and multifactorial stage that can cause a series of detrimental effects, including oxidative stress, inflammation, and mitochondrial dysfunction, which eventually contributes to neuronal apoptosis and inhibits axon regeneration and nerve recovery [4][5][6]. Therefore, effective prevention of detrimental secondary events by reduction of neuronal cell death and promotion of axon regeneration is a potential approach for improving functional recovery after SCI.…”

Section: Introductionmentioning

confidence: 99%

Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule

Wang

Zheng

Han

et al. 2020

Oxidative Medicine and Cellular Longevity

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Spinal cord injury (SCI) is a devastating disease that may lead to lifelong disability. Thus, seeking for valid drugs that are beneficial to promoting axonal regrowth and elongation after SCI has gained wide attention. Metformin, a glucose-lowering agent, has been demonstrated to play roles in various central nervous system (CNS) disorders. However, the potential protective effect of metformin on nerve regeneration after SCI is still unclear. In this study, we found that the administration of metformin improved functional recovery after SCI through reducing neuronal cell apoptosis and repairing neurites by stabilizing microtubules via PI3K/Akt signaling pathway. Inhibiting the PI3K/Akt pathway with LY294002 partly reversed the therapeutic effects of metformin on SCI in vitro and vivo. Furthermore, metformin treatment weakened the excessive activation of oxidative stress and improved the mitochondrial function by activating the nuclear factor erythroid-related factor 2 (Nrf2) transcription and binding to the antioxidant response element (ARE). Moreover, treatment with Nrf2 inhibitor ML385 partially abolished its antioxidant effect. We also found that the Nrf2 transcription was partially reduced by LY294002 in vitro. Taken together, these results revealed that the role of metformin in nerve regeneration after SCI was probably related to stabilization of microtubules and inhibition of the excessive activation of Akt-mediated Nrf2/ARE pathway-regulated oxidative stress and mitochondrial dysfunction. Overall, our present study suggests that metformin administration may provide a potential therapy for SCI.

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“…We found that (a) AS-IV promotes autophagy and inhibits neuronal apoptosis after SCI. 8,[23][24][25] Numerous studies have targeted these two pathological processes for SCI therapy; however, barely any therapies could target both these two pathological processes. In our study, we found that AS-IV possesses 'one stone two birds' potential, which not only inhibits neuronal apoptosis but also suppresses neuroinflammation through inhibiting the mTORC1 signalling pathway (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

Dual regulation of microglia and neurons by Astragaloside IV‐mediated mTORC1 suppression promotes functional recovery after acute spinal cord injury

Lin

Pan

Huang

et al. 2019

J Cellular Molecular Medi

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Inflammation and neuronal apoptosis contribute to the progression of secondary injury after spinal cord injury (SCI) and are targets for SCI therapy; autophagy is reported to suppress apoptosis in neuronal cells and M2 polarization may attenuate inflammatory response in microglia, while both are negatively regulated by mTORC1 signalling. We hypothesize that mTORC1 suppression may have dual effects on inflammation and neuronal apoptosis and may be a feasible approach for SCI therapy. In this study, we evaluate a novel inhibitor of mTORC1 signalling, Astragaloside IV (AS‐IV), in vitro and in vivo. Our results showed that AS‐IV may suppress mTORC1 signalling both in neuronal cells and microglial cells in vitro and in vivo. AS‐IV treatment may stimulate autophagy in neuronal cells and protect them against apoptosis through autophagy regulation; it may also promote M2 polarization in microglial cells and attenuate neuroinflammation. In vivo, rats were intraperitoneally injected with AS‐IV (10 mg/kg/d) after SCI, behavioural and histological evaluations showed that AS‐IV may promote functional recovery in rats after SCI. We propose that mTORC1 suppression may attenuate both microglial inflammatory response and neuronal apoptosis and promote functional recovery after SCI, while AS‐IV may become a novel therapeutic medicine for SCI.

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Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury

Cited by 166 publications

References 79 publications

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule

Dual regulation of microglia and neurons by Astragaloside IV‐mediated mTORC1 suppression promotes functional recovery after acute spinal cord injury

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