Myelin Cx3cr1

Microglial Na/H exchanger-1 (NHE1) protein, encoded by Slc9a1, plays a role in white matter demyelination of ischemic stroke brains. To explore underlying mechanisms, we conducted single cell RNA-seq transcriptome analysis in conditional Slc9a1 knockout (cKO) and wild-type (WT) mouse white matter tissues at 3 days post-stroke. Compared to WT, Nhe1 cKO brains expanded a microglial subgroup with elevated transcription of white matter myelination genes including Spp1, Lgals3, Gpnmb, and Fabp5. This subgroup also exhibited more acidic pHi and significantly upregulated CREB signaling detected by ingenuity pathway analysis and flow cytometry...

Oligodendrocyte death is common in aging and neurodegenerative diseases. In these conditions, single dying oligodendrocytes must be efficiently removed to allow remyelination and prevent a feed-forward degenerative cascade. Here we used a single-cell cortical demyelination model combined with longitudinal intravital imaging of dual-labeled transgenic mice to investigate the cellular dynamics underlying how brain resident microglia remove these cellular debris. Following phagocytic engagement, single microglia cleared the targeted oligodendrocyte and its myelin sheaths in one day via a precise, rapid, and stereotyped sequence...

Non-neuronal cells constitute 90%-95% of sensory ganglia. These cells, especially glial and immune cells, play critical roles in the modulation of sensory neurons. This study aimed to identify, profile, and summarize the types of trigeminal ganglion (TG) non-neuronal cells in naïve male mice using published and our own data generated by single-cell RNA sequencing, flow cytometry, and immunohistochemistry. TG has five types of non-neuronal cells, namely, glial, fibroblasts, smooth muscle, endothelial, and immune cells...

INTRODUCTION: In multiple sclerosis (MS), chronic disability primarily stems from axonal and neuronal degeneration, a condition resistant to conventional immunosuppressive or immunomodulatory treatments. Recent research has indicated that selective sphingosine-1-phosphate receptor S1PR-1 and -5 modulators yield positive effects in progressive MS and mechanistic models of inflammation-driven neurodegeneration and demyelination. METHODS: In this study, the S1PR-1/-5 modulator RP-101074 was evaluated as a surrogate for ozanimod in the non-inflammatory, primary degenerative animal model of light-induced photoreceptor loss (LI-PRL) in CX3CR1-GFP mice to assess potential neuroprotective effects, independent of its immunomodulatory mechanism of action...

Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is critical in restricting neurotropic murine-β-coronavirus, RSA59 infection. RSA59 intracranial injection of Ifit2-deficient (-/-) compared to wild-type (WT) mice results in impaired acute microglial activation, reduced CX3CR1 expression, limited migration of peripheral lymphocytes into the brain, and impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence during the chronic demyelinating phase of RSA59 infection...

Demyelinating disorders of the central nervous system (CNS) occur when myelin and oligodendrocytes are damaged or lost. Remyelination and regeneration of oligodendrocytes can be achieved from endogenous oligodendrocyte precursor cells (OPCs) that reside in the adult CNS tissue. Using a cuprizone mouse model of demyelination, we show that infusion of fractalkine (CX3CL1) into the demyelinated murine brain increases de novo oligodendrocyte formation and enhances remyelination in the corpus callosum and cortical gray matter...

Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+ /H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact...

Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human polymorphic CX3CR1I249/M280 (hCX3CR1I249/M280 ) variant increases disease progression in models of MS. However, the role of hCX3CR1I249/M280 variant on microglial activation and central nervous system repair mechanisms remains unknown. Therefore, using transgenic mice expressing the hCX3CR1I249/M280 variant, we aimed to determine the contribution of defective CX3CR1 signaling to neuroinflammation and remyelination in the cuprizone model of focal demyelination...

BACKGROUND: Major Depressive Disorder (MDD) is a complex and heterogenous psychiatric disorder affecting more than 300 million people worldwide. Though the mechanisms underlying MDD are not fully understood, a subset of depressive patients can manifest chronic neuroinflammatory responses. In addition, brain-imaging studies in MDD patients have provided evidence of white matter reductions and such changes are hypothesized to lead to disruption of Oligodendroglial-Lineage cells (OLN) homeostatic mechanisms, resulting in destabilization of emotional/cognitive circuitry...

Recent research indicates that after spinal cord injury (SCI), microglia accumulate at the borders of lesions between astrocytic and fibrotic scars and perform inflammation-limiting and neuroprotective functions, however, the mechanism of microglial migration remains unclear. Fascin-1 is a key actin-bundling protein that regulates cell migration, invasion and adhesion, but its role during SCI has not been reported. Here, we found that at 7-14 days after SCI in mice, Fascin-1 is significantly upregulated, mainly distributed around the lesion, and specifically expressed in CX3CR1-positive microglia...

Emerging roles for microglia in modifying normal brain development continue to provide new perspectives on the functions of this resident immune cell in the brain. While the molecular underpinnings driving microglia's position in regulating developmental programs remain largely an unchartered territory, innate immune signaling lies at the forefront. At least three innate immune receptors expressed on microglia-fractalkine, complement, and triggering receptor expressed on microglia (TREM2)-modulate developmental synaptic pruning to refine brain circuitry...

Neural and oligodendrocyte precursor cells (NPCs and OPCs) in the subventricular zone (SVZ) of the brain contribute to oligodendrogenesis throughout life, in part due to direct regulation by chemokines. The role of the chemokine fractalkine is well established in microglia; however, the effect of fractalkine on SVZ precursor cells is unknown. We show that murine SVZ NPCs and OPCs express the fractalkine receptor (CX3CR1) and bind fractalkine. Exogenous fractalkine directly enhances OPC and oligodendrocyte genesis from SVZ NPCs in vitro...

BACKGROUND: Doxorubicin (DOX), a widely used chemotherapeutic agent, can cause neurodegeneration in the brain, which leads to a condition known as chemobrain. In fact, chemobrain is a deteriorating condition which adversely affects the lives of cancer survivors. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) and their derived exosomes (BMSCs-Exo) in DOX-induced chemobrain in rat models. METHODS: Chemobrain was induced by exposing rats to DOX (2 mg/kg, i...

V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) that is involved in T-cell quiescence, inhibition of T-cell activation, and in myeloid cells regulates cytokine production, chemotaxis, phagocytosis, and tolerance induction. In the central nervous system (CNS), VISTA is expressed by microglia, the resident macrophage of the parenchyma, and expression is decreased during neuroinflammation; however, the function of VISTA in microglia is unknown...

BACKGROUND: Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6...

Multiple sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that usually presents in young adults and predominantly in females. Microglia, a major resident immune cell in the CNS, are critical players in both CNS homeostasis and disease. We have previously demonstrated that microglia can be efficiently depleted by the administration of tamoxifen in Cx3cr1 CreER/+ Rosa26 DTA/+ mice, with ensuing repopulation deriving from both the proliferation of residual CNS resident microglia and the engraftment of peripheral monocyte-derived microglia-like cells...

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach...

Increased concentrations of unconjugated bilirubin (UCB), namely its free fraction (Bf), in neonatal life may cause transient or definitive injury to neurons and glial cells. We demonstrated that UCB damages neurons and glial cells by compromising oligodendrocyte maturation and myelination, and by activating astrocytes and microglia. Immature neurons and astrocytes showed to be especially vulnerable. However, whether microglia susceptibility to UCB is also age-related was never investigated. We developed a microglia culture model in which cells at 2 days in vitro (2DIV) revealed to behave as the neonatal microglia (amoeboid/reactive cells), in contrast with those at 16DIV microglia that performed as aged cells (irresponsive/dormant cells)...

White matter lesions are common when global cerebral ischemia (GCI) occurs in the elderly, and cause damage to neurological and psychological functions. Remyelination often fails because of the limited recruitment of oligodendrocyte progenitor cells (OPCs) to the demyelinated site or the inefficient differentiation of OPCs to mature oligodendrocytes (OLs). The activation of microglia, the most important immune cells in the central nervous system, and subsequent inflammation have been implicated in myelination repair disorder...

OBJECTIVE: Chronic neuropathic pain (NP) has become a worldwide public health problem. This study was aimed to establish graded NP model to investigate the effect of CREB1 on nerve repair and NP after peripheral nerve injury. MATERIALS AND METHODS: Based on NP model, we measured the 50% paw withdrawal threshold (PWT) of rat hind paws and sciatic functional index (SFI). Luxol fast blue staining was performed to measure the ratio of distal myelin sheath to proximal (DPR)...