Phagocytosis Of Myelin Debris Research Articles

Phospholipase D Family Member 4 Regulates Microglial Phagocytosis and Remyelination via the AKT Pathway in a Cuprizone-Induced Multiple Sclerosis Mouse Model.

Remyelination is an endogenous repair process that is often deficient in multiple sclerosis (MS). Stimulation of remyelination is thought to help limit the progression of MS. This study aimed to investigate the expression pattern and function of a microglial phagocytosis-related gene, phospholipase D family member 4 (PLD4), in a cuprizone (CPZ)-induced MS mouse model. The extent of remyelination was assessed using LFB staining. Myelin phagocytosis assay was used to investigate the effect of Pld4 on microglial phagocytic activity. Pld4 was upregulated in the corpus callosum during demyelination and remyelination. AAV9-mediated Pld4 deficiency impaired remyelination and reduced the number of Olig2-positive cells. In the corpus callosum of Pld4-deficient mice, the microglial phagocytosis marker MAC2 was reduced, accompanied by inhibition of TrkA/AKT signaling. Similarly, the phagocytosis assay showed that Pld4 knockdown significantly inhibited myelin debris phagocytosis by BV2 cells. The AKT activator SC79 reversed the Pld4 deficiency-induced inhibition of microglial phagocytic activity and rescued the impaired remyelination in Pld4-deficient mice. PLD4 is upregulated in CPZ-induced MS and modulates microglial phagocytosis and remyelination via the AKT pathway. Our findings provide experimental evidence for a better understanding of the molecular mechanism of MS.

Myelin debris phagocytosis in demyelinating disease.

Demyelinating diseases are often caused by a variety of triggers, including immune responses, viral infections, malnutrition, hypoxia, or genetic factors, all of which result in the loss of myelin in the nervous system. The accumulation of myelin debris at the lesion site leads to neuroinflammation and inhibits remyelination; therefore, it is crucial to promptly remove the myelin debris. Initially, Fc and complement receptors on cellular surfaces were the primary clearance receptors responsible for removing myelin debris. However, subsequent studies have unveiled the involvement of additional receptors, including Mac-2, TAM receptors, and the low-density lipoprotein receptor-related protein 1, in facilitating the removal process. In addition to microglia and macrophages, which serve as the primary effector cells in the disease phase, a variety of other cell types such as astrocytes, Schwann cells, and vascular endothelial cells have been demonstrated to engage in the phagocytosis of myelin debris. Furthermore, we have concluded that oligodendrocyte precursor cells, as myelination precursor cells, also exhibit this phagocytic capability. Moreover, our research group has innovatively identified the low-density lipoprotein receptor as a potential phagocytic receptor for myelin debris. In this article, we discuss the functional processes of various phagocytes in demyelinating diseases. We also highlight the alterations in signaling pathways triggered by phagocytosis, and provide a comprehensive overview of the various phagocytic receptors involved. Such insights are invaluable for pinpointing potential therapeutic strategies for the treatment of demyelinating diseases by targeting phagocytosis.

Repeated trans-spinal magnetic stimulation promotes microglial phagocytosis of myelin debris after spinal cord injury through LRP-1

Spinal cord injury (SCI) is a serious trauma of the central nervous system. The clearance of myelin debris is a critical step in the functional recovery following spinal cord injury (SCI). Recent studies have begun to reveal critical roles for professional phagocytes in the central nervous system, microglia, and their receptors in the control of myelin debris in neurodegenerative disease. Repeated trans-spinal magnetic stimulation (rTSMS) has been demonstrated as a noninvasive SCI treatment that enhances tissue repair and functional recovery. In this study, we investigated the role and molecular mechanism of rTSMS on microglial phagocytosis of myelin debris in a rat SCI model. In our studies, we found that rTSMS significantly promoted the motor function recovery of SCI rats associated with the inhibition the neuroinflammation and glia scar formation. Immunofluorescence results further showed that the rTSMS promotes the clearance of myelin debris by microglia in vivo and in vitro. Additionally, receptor-associated protein (RAP), a Low-density lipoprotein receptor-related protein-1 (LRP-1) inhibitor, could cancel the accelerated microglial phagocytosis of myelin debris after rTSMS in vitro experiments. Simultaneously, Elisa's results and western blotting respectively showed that rTSMS significantly decreased the levels of soluble LRP-1(sLRP-1) and the LRP-1 splicing enzyme of ADAM17. In conclusion, rTSMS could promote the clearance of myelin debris by microglia through LRP-1 to improve the functional recovery of SCI rats.

V-ATPase B2 promotes microglial phagocytosis of myelin debris by inactivating the MAPK signaling pathway

Microglial phagocytosis of myelin debris is a crucial process for promoting myelin regeneration in conditions such as multiple sclerosis (MS). Vacuolar-ATPase B2 (V-ATPase B2) has been implicated in various cellular processes, but its role in microglial phagocytosis and its potential impact on MS-related responses remain unclear. In this study, we employed BV-2 murine microglial cells to investigate the influence of V-ATPase B2 on the phagocytosis of myelin debris by microglia. The results revealed that V-ATPase B2 expression increased in response to myelin debris exposure. Overexpression of V-ATPase B2 significantly enhanced BV-2 phagocytosis of myelin debris. Additionally, V-ATPase B2 overexpression shifted microglial polarization towards an anti-inflammatory M2 phenotype, coupled with decreased lysosomal pH and enhanced lysosome degradation capacity. Moreover, endoplasmic reticulum (ER) stress inhibitor, 4-PBA, reversed the effects of V-ATPase B2 silencing on ER stress, M2 polarization, and lysosomal degradation of BV-2 cells. The MAPK pathway was inhibited upon V-ATPase B2 overexpression, contributing to heightened myelin debris clearance by BV-2 cells. Notably, MAPK pathway inhibition partially attenuated the inhibitory effects of V-ATPase B2 knockdown on myelin debris clearance. In conclusion, our findings reveal a pivotal role for V-ATPase B2 in promoting microglial phagocytosis of myelin debris by regulating microglial polarization and lysosomal function via the MAPK signaling pathway, suggesting that targeting V-ATPase B2 may hold therapeutic potential for enhancing myelin debris clearance and modulating microglial responses in MS and related neuroinflammatory disorders.

Effect of Myelin Debris on the Phenotypic Transformation of Astrocytes after Spinal Cord Injury in Rats

After spinal cord injury (SCI), the accumulation of myelin debris can serve as proinflammatory agents, hindering axon regrowth and exacerbating damage. While astrocytes have been implicated in the phagocytosis of myelin debris, the impact of this process on the phenotypic transformation of astrocytes and their characteristics following SCI in rats is not well understood. Here, we demonstrated that the conditioned medium of myelin debris can trigger apoptosis in rat primary astrocytes in vitro. Using a compressional SCI model in rats, we observed that astrocytes can engulf myelin debris through ATP-binding cassette transporter sub-family A member 1 (ABCA1), and these engulfed cells tend to transform into A1 astrocytes, as indicated by C3 expression. At 4 days post-injury (dpi), astrocytes rapidly transitioned into A1 astrocytes and maintained this phenotype from 4 to 28 dpi, while A2 astrocytes, characterized by S100, were only detected at 14 and 28 dpi. Reactive astrocytes, identified by Nestin, emerged at 4 and 7 dpi, whereas scar-forming astrocytes, marked by N-cadherin, were evident at 14 and 28 dpi. This study illustrates the distribution patterns of astrocyte subtypes and the potential interplay between astrocytes and myelin debris after SCI in rats. We emphasize that myelin debris can induce astrocyte apoptosis in vitro and promote the transformation of astrocytes into A1 astrocytes in vivo. These two classification methods are not mutually exclusive, but rather complementary.

Serum LDL Promotes Microglial Activation and Exacerbates Demyelinating Injury in Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.

The astrocytic phagocytosis of myelin debris and reactive characteristics in vivo and in vitro

The astrocytic phagocytosis of myelin debris and reactive characteristics in vivo and in vitro

Targeted transplantation of engineered mitochondrial compound promotes functional recovery after spinal cord injury by enhancing macrophage phagocytosis

Mitochondria are crucial in sustaining and orchestrating cellular functions. Capitalizing on this, we explored mitochondrial transplantation as an innovative therapeutic strategy for acute spinal cord injury (SCI). In our study, we developed an engineered mitochondrial compound tailored to target macrophages within the SCI region. Sourced from IL-10-induced Mertkhi bone marrow-derived macrophages, we conjugated a peptide sequence, cations-cysteine-alanine-glutamine-lysine (CAQK), with the mitochondria, optimizing its targeting affinity for the injury site. Our data demonstrated that these compounds significantly enhanced macrophage phagocytosis of myelin debris, curtailed lipid buildup, ameliorated mitochondrial dysfunction, and attenuated pro-inflammatory profiles in macrophages, both in vitro and in vivo. The intravenously delivered mitochondrial compounds targeted the SCI epicenter, with macrophages being the primary recipients. Critically, they promoted tissue regeneration and bolstered functional recovery in SCI mice. This study heralds a transformative approach to mitochondrial transplantation in SCI, spotlighting the modulation of macrophage activity, phagocytosis, and phenotype.

Astrocytic phagocytosis of myelin debris and reactive characteristics in vivo and in vitro.

Persistent myelin debris can inhibit axonal regeneration, thereby hindering remyelination. Effective removal of myelin debris is essential to eliminate the interference of myelin debris in oligodendrocyte progenitor cell (OPC) activation, recruitment to demyelinating sites and/or differentiation into mature oligodendrocytes (OLs). In addition to microglia, it has been reported that astrocytic phagocytosis of myelin debris is a feature of early demyelination. In the present study, astrocytes effectively phagocytized myelin debris in vitro and in vivo. On the 5th day after injecting myelin debris into the brain, astrocytes were enriched in the area injected with myelin debris compared with microglia, and their ability to engulf myelin debris was stronger than that of microglia. When exposed to myelin debris, astrocytes phagocytizing myelin debris triggered self-apoptosis, accompanied by the activation of NF-κB, down-regulation of Nrf2, and the increase of ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF). However, the activation of astrocytic NF-κB did not influence the inflammatory cytokines IL-1β, IL-6, and TNF-α, and the anti-inflammatory factor IL-10. The proliferation of astrocytes and mobilization of OPCs in the subventricular zone were elevated on the 5th day after intracerebral injection of myelin debris. The results suggested that myelin phagocytosis of astrocytes should help improve the microenvironment and promote myelin regeneration by increasing CNTF and bFGF within the central nervous system. However, the molecular interaction of astrocytes acting as phagocytes remains to be further explored. Therefore, an improvement of astrocytes to phagocytize myelin debris may be a promising treatment measure to prevent demyelination and promote remyelination in MS and other diseases with prominent myelin injury.

Deletion of CD47 from Schwann cells and macrophages hastens myelin disruption/dismantling and scavenging in Schwann cells and augments myelin debris phagocytosis in macrophages

BackgroundMyelin that surrounds axons breaks in trauma and disease; e.g., peripheral nerve and spinal cord injuries (PNI and SCI) and multiple sclerosis (MS). Resulting myelin debris hinders repair if not effectively scavenged by Schwann cells and macrophages in PNI and by microglia in SCI and MS. We showed previously that myelin debris evades phagocytosis as CD47 on myelin ligates SIRPα (signal regulatory protein-α) on macrophages and microglia, triggering SIRPα to inhibit phagocytosis in phagocytes. Using PNI as a model, we tested the in vivo significance of SIRPα-dependent phagocytosis inhibition in SIRPα null mice, showing that SIRPα deletion leads to accelerated myelin debris clearance, axon regeneration and recovery of function from PNI. Herein, we tested how deletion of CD47, a SIRPα ligand and a cell surface receptor on Schwann cells and phagocytes, affects recovery from PNI.MethodsUsing CD47 null (CD47−/−) and wild type mice, we studied myelin disruption/dismantling and debris clearance, axon regeneration and recovery of function from PNI.ResultsAs expected from CD47 on myelin acting as a SIRPα ligand that normally triggers SIRPα-dependent phagocytosis inhibition in phagocytes, myelin debris clearance, axon regeneration and function recovery were all faster in CD47−/− mice than in wild type mice. Unexpectedly compared with wild type mice, myelin debris clearance started sooner and CD47-deleted Schwann cells displayed enhanced disruption/dismantling and scavenging of myelin in CD47−/− mice. Furthermore, CD47-deleted macrophages from CD47−/− mice phagocytosed more myelin debris than CD47-expressing phagocytes from wild type mice.ConclusionsThis study reveals two novel normally occurring CD47-dependent mechanisms that impede myelin debris clearance. First, CD47 expressed on Schwann cells inhibits myelin disruption/dismantling and debris scavenging in Schwann cells. Second, CD47 expressed on macrophages inhibits myelin debris phagocytosis in phagocytes. The two add to a third mechanism that we previously documented whereby CD47 on myelin ligates SIRPα on macrophages and microglia, triggering SIRPα-dependent phagocytosis inhibition in phagocytes. Thus, CD47 plays multiple inhibitory roles that combined impede myelin debris clearance, leading to delayed recovery from PNI. Similar inhibitory roles in microglia may hinder recovery from other pathologies in which repair depends on efficient phagocytosis (e.g., SCI and MS).

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

The Protective Effect of Ginkgolide K on Astrocytes Exposed to Myelin Debris in vitro and Demyelination in vivo

Background Ginkgolide K ( GK) has a protective effect on neurons and myelin sheath, and the function of astrocytes in phagocytizing myelin debris has attracted extensive attention in remyelination. Objectives This study focuses on the impact of GK on the phagocytosis of myelin debris by astrocytes and explores the possibility of treating demyelination. Materials and Methods Male C57BL/6 mice were used to establish a cuprizone (CPZ)-induced demyelination model. After being fed a normal or CPZ diet for 4 weeks, mice were intraperitoneally injected with PEG400 or GK for 14 consecutive days. GL261 and primary astrocytes were exposed to myelin debris. Immunohistochemistry/immunocytochemistry staining, western blot, RT-PCR, and other methods were used to detect the relevant indicators. Results Astrocytes engulfed myelin debris, leading to astrocyte reactivity with increased p-NF-kB/p65 and ATF6 expression and decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression, which was reversed by GK. Subsequently, astrocytes stimulated by myelin debris underwent self-apoptosis with increased expression of caspase-3 and BCL2-associated X (Bax), which was inhibited by GK. Simultaneously, GK efficiently promoted astrocytes to increase the production of neurotrophic ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF), speculating that increased CNTF/bFGF, decreased p-NF-kB/p65/ATF6, and up-regulated Nrf2 should participate in the protection of astrocyte apoptosis and build a beneficial microenvironment for myelin regeneration. Conclusion The results suggest that GK may have the potential to treat demyelination by promoting debris clearance and improving the brain microenvironment. However, further studies are needed to understand the physiological and pathological consequences of astrocytic phagocytosis and to investigate the possibility of using GK as a therapeutic application.

Ablation of microglia following infection of the central nervous system with a neurotropic murine coronavirus infection leads to increased demyelination and impaired remyelination

Intracranial inoculation of susceptible mice with a glial-tropic strain of mouse hepatitis virus (JHMV), a murine coronavirus, results in an acute encephalomyelitis followed by viral persistence in white matter tracts accompanied by chronic neuroinflammation and demyelination. Microglia are the resident immune cell of the central nervous system (CNS) and are considered important in regulating events associated with neuroinflammation as well as influencing both white matter damage and remyelination. To better understand mechanisms by which microglia contribute to these immune-mediated events, JHMV-infected mice with established demyelination were treated with the small molecular inhibitor of colony stimulating factor 1 receptor (CSF1R), PLX5622, to deplete microglia. Treatment with PLX5622 did not affect viral replication within the CNS yet the severity of demyelination was increased and remyelination impaired compared to control mice. Gene expression analysis revealed that targeting microglia resulted in altered expression of genes associated with immune cell activation and phagocytosis of myelin debris. These findings indicate that microglia are not critical in viral surveillance in persistently JHMV-infected mice yet restrict white matter damage and remyelination, in part, by influencing phagocytosis of myelin debris.

Construction and optimization of a coculture system of mouse brain microvascular endothelial cells and myelin debris

Microvascular endothelial cells are a newly discovered cell type involved in the phagocytosis of myelin debris, which play a key role in the repair of spinal cord injuries. Several methods for the preparation of myelin debris and parameters for constructing a coculture system of microvascular endothelial cells and myelin debris are available, but no systematic studies have yet been conducted, which hinders further exploration of the mechanisms of demyelinating disease repair. Herein, we aimed to develop a standardized method for this process. Myelin debris of different sizes was obtained from the brains of C57BL/6 mice by stripping the brains under aseptic conditions, multiple grinding, gradient centrifugation, etc. Transmission electron microscopy and nanoparticle size analysis were used to characterize myelin debris. Microvascular endothelial cells were cultured on a matrix gel, and myelin debris of different sizes (fluorescently labeled using CFSE) was placed in coculture after forming a vascular-like structure. Subsequently, myelin debris of different concentrations was cocultured in the vascular-like structure, and phagocytosis of myelin debris by microvascular endothelial cells was detected using immunofluorescence staining and flow cytometry. We found that myelin debris could be successfuly obtained from the mouse brain with secondary grinding and other steps and cocultured with microvascular endothelial cells at a concentration of 2 mg/mL, which promoted the phagocytosis of microvascular endothelial cells. In conclusion, we provide a reference for the protocol of a coculture system of microvascular endothelial cells and myelin debris.

Quantitative biochemical phenotypic heterogeneity of macrophages after myelin debris phagocytosis at a single cell level by synchrotron radiation fourier transform infrared microspectroscopy

During the immuno-inflammatory pathophysiological process of spinal cord injury, traumatic brain injury, and ischemic stroke, macrophages play an important role in phagocytizing and clearing degenerated myelin debris. After phagocytizing myelin debris, the biochemical phenotypes related to the biological function of macrophages show vast heterogeneity; however, it is not fully understood. Detecting biochemical changes after myelin debris phagocytosis by macrophages at a single-cell level is helpful to characterize phenotypic and functional heterogeneity. In this study, based on the cell model of myelin debris phagocytosis by macrophages in vitro, the biochemical changes in macrophages were investigated using Synchrotron radiation-based Fourier transform infrared (SR-FTIR) microspectroscopy. Infrared spectrum fluctuations, principal component analysis, and cell-to-cell Euclidean distance statistical analysis of specific spectrum regions revealed dynamic and significant changes in proteins and lipids within macrophages after myelin debris phagocytosis. Thus, SR-FTIR microspectroscopy is a powerful identification toolkit for exploring biochemical phenotype heterogeneity transformation that may be of great importance to providing an evaluation strategy for studying cell functions related to cellular substance distribution and metabolism.

Remyelination in multiple sclerosis from the miRNA perspective.

Remyelination relies on the repair of damaged myelin sheaths, involving microglia cells, oligodendrocyte precursor cells (OPCs), and mature oligodendrocytes. This process drives the pathophysiology of autoimmune chronic disease of the central nervous system (CNS), multiple sclerosis (MS), leading to nerve cell damage and progressive neurodegeneration. Stimulating the reconstruction of damaged myelin sheaths is one of the goals in terms of delaying the progression of MS symptoms and preventing neuronal damage. Short, noncoding RNA molecules, microRNAs (miRNAs), responsible for regulating gene expression, are believed to play a crucial role in the remyelination process. For example, studies showed that miR-223 promotes efficient activation and phagocytosis of myelin debris by microglia, which is necessary for the initiation of remyelination. Meanwhile, miR-124 promotes the return of activated microglia to the quiescent state, while miR-204 and miR-219 promote the differentiation of mature oligodendrocytes. Furthermore, miR-138, miR-145, and miR-338 have been shown to be involved in the synthesis and assembly of myelin proteins. Various delivery systems, including extracellular vesicles, hold promise as an efficient and non-invasive way for providing miRNAs to stimulate remyelination. This article summarizes the biology of remyelination as well as current challenges and strategies for miRNA molecules in potential diagnostic and therapeutic applications.

Lentinan alleviates sciatic nerve injury by promoting autophagy to remove myelin fragments.

Lentinan, a natural drug with wide-ranging pharmacological activities, can regulate autophagy-the process through which Schwann cells (SCs) eliminate myelin fragments after peripheral nerve injury (PNI). However, the effect of lentinan after PNI and the role of accelerated myelin debris removal via autophagy in this process are unclear. This study examined the effect of lentinan on rat sciatic nerve repair following crush injury and the underlying mechanisms. After the successful establishment of the sciatic nerve compression injury model, group-specific treatments were performed. The treatment group received 20 mg/kg lentinan via intraperitoneal injection, while the model group was treated with normal saline. The recovery in each group was then evaluated. Further, a rat SC line (RSC96) was cultured in medium with/without lentinan after supplementation with homogenous myelin fractions to evaluate the removal of myelin particles. Our results showed that lentinan promotes autophagic flux in vivo via the AMPK/mTOR signaling pathway, accelerates the clearance of myelin debris by SCs, and inhibits neuronal apoptosis, thereby promoting neurological recovery. Similarly, in vitro experiments showed that lentinan promotes the phagocytosis of myelin debris by SCs. In conclusion, our results suggest that lentinan primarily promotes nerve regeneration by accelerating the autophagic clearance of myelin debris in SCs, and this process is likely regulated by the AMPK/mTOR signaling pathway. Therefore, this study provides compelling evidence that lentinan may be a cost-effective and natural treatment agent for PNI.

Astrocytic CXCL5 hinders microglial phagocytosis of myelin debris and aggravates white matter injury in chronic cerebral ischemia

BackgroundChronic cerebral ischemia induces white matter injury (WMI) contributing to cognitive decline. Both astrocytes and microglia play vital roles in the demyelination and remyelination processes, but the underlying mechanism remains unclear. This study aimed to explore the influence of the chemokine CXCL5 on WMI and cognitive decline in chronic cerebral ischemia and the underlying mechanism.MethodsBilateral carotid artery stenosis (BCAS) model was constructed to mimic chronic cerebral ischemia in 7–10 weeks old male mice. Astrocytic Cxcl5 conditional knockout (cKO) mice were constructed and mice with Cxcl5 overexpressing in astrocytes were generated by stereotactic injection of adeno-associated virus (AAV). WMI was evaluated by magnetic resonance imaging (MRI), electron microscopy, histological staining and western blotting. Cognitive function was examined by a series of neurobehavioral tests. The proliferation and differentiation of oligodendrocyte progenitor cells (OPCs), phagocytosis of microglia were analyzed via immunofluorescence staining, western blotting or flow cytometry.ResultsCXCL5 was significantly elevated in the corpus callosum (CC) and serum in BCAS model, mainly expressed in astrocytes, and Cxcl5 cKO mice displayed improved WMI and cognitive performance. Recombinant CXCL5 (rCXCL5) had no direct effect on the proliferation and differentiation of OPCs in vitro. Astrocytic specific Cxcl5 overexpression aggravated WMI and cognitive decline induced by chronic cerebral ischemia, while microglia depletion counteracted this effect. Recombinant CXCL5 remarkably hindered microglial phagocytosis of myelin debris, which was rescued by inhibition of CXCL5 receptor C-X-C motif chemokine receptor 2 (CXCR2).ConclusionOur study revealed that astrocyte-derived CXCL5 aggravated WMI and cognitive decline by inhibiting microglial phagocytosis of myelin debris, suggesting a novel astrocyte-microglia circuit mediated by CXCL5-CXCR2 signaling in chronic cerebral ischemia.

TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection.

Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.

Consequences and mechanisms of myelin debris uptake and processing by cells in the central nervous system

Central nervous system (CNS) disorders and trauma involving changes to the neuronal myelin sheath have long been a topic of great interest. One common pathological change in these diseases is the generation of myelin debris resulting from the breakdown of the myelin sheath. Myelin debris contains many inflammatory and neurotoxic factors that inhibit remyelination and make its clearance a prerequisite for healing in CNS disorders. Many professional and semiprofessional phagocytes participate in the clearance of myelin debris in the CNS. These cells use various mechanisms for the uptake of myelin debris, and each cell type produces its own unique set of pathologic consequences resulting from the debris uptake. Examining these cells’ phagocytosis of myelin debris will contribute to a more complete understanding of CNS disease pathogenesis and help us conceptualize how the necessary clearance of myelin debris must be balanced with the detrimental consequences brought about by its clearance.