Distinctive functional deficiencies in axonal conduction associated with two forms of cerebral white matter injury

Mu, Hongfeng; Gao, Xuguang; Li, Sicheng; Wei, Pengju; Zhao, Yongfang; Zhang, Wenting; Wang, Yun; Gao, Yanqin

doi:10.1111/cns.13155

Cited by 11 publications

(8 citation statements)

References 49 publications

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“…To determine whether the white matter structural remodeling was associated with white matte functional repair, we measured the evoked CAPs in the corpus callosum after 28 days of tMCAO, an electrophysiological examination known as a key method to assess the functional integrity of axons and white matter 50 , 54 . The early peak (N1 component) of CAPs mainly represents the conduction of myelinated axons, while the later phase peak (N2 component) of CAPs mainly signifies the unmyelinated axons, but the amplitudes of both peaks are the combined results of axonal injury and demyelination 55 , 56 .…”

Section: Resultsmentioning

confidence: 99%

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M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice

Liu

Song

et al. 2022

Theranostics

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Rationale: White matter repair is critical for the cognitive and neurological functional recovery after ischemic stroke. M2 microglia are well-documented to enhance remyelination and their extracellular vesicles (EVs) mediate cellular function after brain injury. However, whether M2 microglia-derived EVs could promote white matter repair after cerebral ischemia and its underlying mechanism are largely unknown. Methods: EVs were isolated from IL-4 treated microglia (M2-EVs) and untreated microglia (M0-EVs). Adult ICR mice subjected to 90-minute transient middle cerebral artery occlusion received intravenous EVs treatment for seven consecutive days. Brain atrophy volume, neurobehavioral tests were examined within 28 days following ischemia. Immunohistochemistry, myelin transmission electron microscope and compound action potential measurement were performed to assess white matter structural remodeling, functional repair and oligodendrogenesis. The effects of M2-EVs on oligodendrocyte precursor cells (OPCs) were also examined in vitro . EVs' miRNA sequencing, specific miR-23a-5p knockdown in M2-EVs and luciferase reporter assay were used to explore the underlying mechanism. Results: M2-EVs reduced brain atrophy volume, promoted functional recovery, oligodendrogenesis and white matter repair in vivo , increased OPC proliferation, survival and differentiation in vitro . miR-23a-5p was enriched in M2-EVs and could promote OPC proliferation, survival and maturation, while knocking down miR-23a-5p in M2-EVs reversed the beneficial effects of M2-EVs both in vitro and in vivo . Luciferase reporter assay showed that miR-23a-5p directly targeted Olig3. Conclusion: Our results demonstrated that M2 microglia could communicate to OPCs through M2-EVs and promote white matter repair via miR-23a-5p possibly by directly targeting Olig3 after ischemic stroke, suggesting M2-EVs is a novel and promising therapeutic strategy for white matter repair in stroke and demyelinating disease.

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Section: Resultsmentioning

confidence: 99%

“…CAP measurement in the corpus callosum were carried out after 28 days of tMCAO as previously described 50 . Briefly, after anesthesia and cardiac perfusion of ice cutting fluid, mice brains were quickly removed and cut into 350 μm coronal slices using a Vibratome (Leica).…”

Section: Methodsmentioning

confidence: 99%

M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice

Liu

Song

et al. 2022

Theranostics

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“…Ultrastructural observation of white matter demyelination was performed by transmission electron microscopy (TEM) as described previously [ 23 , 24 ]. Briefly, mice were deeply anesthetized with isoflurane (5%) and their brains were quickly removed 35 days after tMCAO.…”

Section: Methodsmentioning

confidence: 99%

Interleukin 13 promotes long-term recovery after ischemic stroke by inhibiting the activation of STAT3

Chen

Huang

Wei

et al. 2022

J Neuroinflammation

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Background Microglia/macrophages are activated after cerebral ischemic stroke and can contribute to either brain injury or recovery by polarizing microglia/macrophage into distinctive functional phenotypes with pro- or anti-inflammatory properties. Interleukin-13 (IL-13) is an anti-inflammatory cytokine that regulates microglia/macrophage polarization toward an anti-inflammatory phenotype. However, it is not clear whether IL-13 is beneficial after ischemic stroke long-term and the underlying molecular mechanism(s) remain unknown. Thus, we examined the effect of IL-13 on long-term recovery and microglia/macrophage polarization in mice with transient middle cerebral artery occlusion model (tMCAO). Methods tMCAO was induced in adult male C57BL/6J mice. IL-13 (60 μg/kg) was administered intranasally starting 2 h after stroke and continued for seven consecutive days. Sensorimotor function, spatial learning and memory function, as well as brain infarct volume were assessed up to 35 days after stroke. White matter integrity was evaluated by electrophysiology, immunofluorescence staining, and transmission electron microscopy. Microglia/macrophage activation was assessed using immunofluorescence staining and quantitative real-time polymerase chain reaction. Changes in immune cells in the brain and the periphery, and expression of IL-13 receptors in different brain cells were detected by flow cytometry. Primary neuron/microglia co-cultures and a STAT3 inhibitor were used for mechanistic studies. Results Post-treatment with IL-13 improved long-term neurofunctional recovery and decreased brain tissue atrophy after stroke. Intranasal delivery of IL-13 enhanced the structural and functional integrity of white matter after stroke. Furthermore, the neuroprotection afforded by IL-13 administration was not due to a direct effect on neurons, but by indirectly regulating the anti-inflammatory phenotype of microglia/macrophages. IL-13 treatment also had no effect on peripheral immune cells. Mechanistically, IL-13 improved the long-term outcome after ischemic stroke by promoting the polarization of microglia/macrophages toward the anti-inflammatory phenotype at least partially by inhibiting the phosphorylation of STAT3. Conclusions IL-13 promotes white matter repair and improves neurofunctional outcomes after ischemic stroke by modulating microglia/macrophages via inhibition of STAT3 phosphorylation.

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“…7h). Compound action potentials (CAPs) represent synchronous firing of numerous axons and previous results from our group showed the N1 peak responded to myelinated axonal conduction and the N2 peak responded to unmyelinated axonal conduction [44] (Fig. 7i).…”

Section: Sik3-cko Promoted Functional Recovery After Tfcimentioning

confidence: 87%

The role of microglial/macrophagic salt-inducible kinase 3 on normal and excessive phagocytosis after transient focal cerebral ischemia

Wang

Chen

et al. 2022

Cell. Mol. Life Sci.

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Previous studies suggested that anti-inflammatory microglia/macrophages (Mi/MΦ) play a role in “normal phagocytosis,” which promoted the rapid clearance of necrotic substances and apoptotic cells. More recently, a few studies have found that Mi/MΦ also play a role in “pathological phagocytosis” in the form of excessive or reduced phagocytosis, thereby worsening damage induced by CNS diseases. However, the underlying mechanisms and the Mi/MΦ subtypes related to this pathological phagocytosis are still unknown. Salt-inducible kinase 3 (SIK3), a member of the 5’ adenosine monophosphate-activated protein kinase (AMPK) family, has been shown to regulate inflammation in several peripheral diseases. Whether SIK3 also regulates the inflammatory response in CNS diseases is currently unknown. Therefore, in this study, we created a transgenic tamoxifen-induced Mi/MΦ-specific SIK3 conditional knockout (SIK3-cKO) mouse to examine SIK3’s role in phagocytotic function induced by transient focal cerebral ischemia (tFCI). By single-cell RNA-seq, we found the pro-inflammatory Mi/MΦ phenotype performed an excessive phagocytotic function, but the anti-inflammatory Mi/MΦ phenotype performed a normal phagocytotic function. We found that SIK3-cKO caused Mi/MΦ heterogenization from the transitional phenotype to the anti-inflammatory phenotype after tFCI. This phenotypic shift corresponded with enhanced phagocytosis of both apoptotic and live neurons. Interestingly, SIK3-cKO enhanced normal phagocytosis of myelin debris but attenuating excessive phagocytosis of non-damaged myelin sheath, thereby protecting white matter integrity after tFCI. CD16, a pro-inflammation marker, was decreased significantly by SIK3-cKO and correlated with “excessive phagocytosis.” SIK3-cKO promoted long-term recovery of white matter function and neurological function as assessed with electrophysiological compound action potential (CAPs) and behavioral analysis. This study is the first to show a role of SIK3 in Mi/MΦ phagocytosis in CNS diseases, and reveals that promoting Mi/MΦ anti-inflammatory heterogenization inhibits “excessive phagocytosis” of live cells and facilitates “normal phagocytosis” of apoptotic cells. Therefore, inhibition of SIK3 in Mi/MΦ may be a potential therapeutic target in stroke and other CNS diseases with accompanying white matter destruction. Graphical abstract In the acute stage of tFCI, Mi/MΦ polarized into different phenotypes. The pro-inflammatory Mi/MΦ phenotype performed an excessive phagocytotic function. In contrast, the anti-inflammatory Mi/MΦ phenotype performed a normal phagocytotic function. After tFCI, SIK3-cKO promoted anti-inflammatory phenotypic heterogenization of Mi/MΦ. SIK3-cKO promoted Mi/MΦ phagocytosis of apoptotic (normal phagocytosis) and living neuronal cell bodies (excessive phagocytosis) in gray matter. Interestingly, SIK3-cKO specifically increased normal phagocytosis of myelin debris concurrent with an attenuation of excessive phagocytosis of myelin sheath in white matter. These changes induced by SIK3-cKO were associated with protection of white matter integrity and long-term neurofunctional recovery after tFCI.

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Distinctive functional deficiencies in axonal conduction associated with two forms of cerebral white matter injury

Cited by 11 publications

References 49 publications

M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice

M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice

Interleukin 13 promotes long-term recovery after ischemic stroke by inhibiting the activation of STAT3

The role of microglial/macrophagic salt-inducible kinase 3 on normal and excessive phagocytosis after transient focal cerebral ischemia

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