CD200
OX-2 membrane glycoprotein precursor (CD200 antigen) [MOX1] [MOX2] [My033]
Publications[править]
Age is the most prominent risk factor for the development of postoperative cognitive dysfunction. This study investigated the potential role of anti-inflammatory interleukin (IL)-4 in age-related differences of surgery-induced cognitive deficits and neuroinflammatory responses. Both adult and aged Sprague-Dawley male rats were subjected to partial hepatectomy or partial hepatectomy with a cisterna magna infusion of IL-4. On postoperative days 1, 3, and 7, the rats were subjected to a reversed Morris water maze test. Hippocampal IL-1β, IL-6, IL-4, and IL-4 receptor (IL-4R) were measured at each time point. Brain derived neurotrophic factor (BDNF), synaptophysin, Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, and CD200 were also examined in the hippocampus. Age induced an exacerbated cognitive impairment and an amplified neuroinflammatory response triggered by surgical stress on postoperative days 1 and 3. A corresponding decline in the anti-inflammatory cytokine IL-4 and BDNF were also found in the aged rats at the same time point. Treatment with IL-4 downregulated the expression of proinflammatory cytokines (e.g., IL-1β and IL-6), increased the levels of BDNF and synaptophysin in the brain and improved the behavioral performance. An increased Arg1 expression and a high level of CD200 were also observed after a cisterna magna infusion of IL-4. An age-related decrease in IL-4 expression exacerbated surgery-induced cognitive deficits and exaggerated the neuroinflammatory responses. Treatment with IL-4 potentially attenuated these effects by enhancing BDNF and synaptophysin expression, inhibiting microglia activation and decreasing the associated production of proinflammatory cytokines.
MeSH Terms
- Aging
- Animals
- Cognitive Dysfunction
- Disease Models, Animal
- Hippocampus
- Inflammation
- Interleukin-4
- Microglia
- Rats, Sprague-Dawley
Keywords
- Aging
- Cytokines
- Hippocampus
- Neuroinflammation
- Postoperative cognitive dysfunction (POCD)
Increasing evidence indicates that stress potentiates pro-inflammatory response to a subsequent peripheral immune challenge. The present study investigated if prior exposure to inescapable tailshock (IS) delayed the recovery of surgery-induced spatial learning and memory impairment and prolonged hippocampus interleukin (IL)-1β and IL-6 expression. A total of 192 aged rats were trained with Morris water-maze (MWM) for 6 consecutive days. A single session of inescapable tailshock was performed on day 6 after training. Then, the rats subjected to partial hepatectomy. Hippocampal-dependent spatial learning and memory were assessed on postoperative days 1, 3 and 7. The cytokines IL-1β and IL-6 and ionized calcium binding adaptor protein (Iba)-1 were measured at each time point. Cluster of differentiation 200 (CD200) was also measured to explore potential mechanisms of glial cell activation. Exposure of IS alone failed to affect the latency to platform and increase hippocampal cytokine levels at each time point. However, IS alone significantly increased the expression levels of Iba-1. A prolonged latency and additional significant increase in hippocampal levels of IL-1β and IL-6 were observed when partial hepatectomy was performed in aged rats exposed to IS 24h later. The combination of IS and surgical trauma dramatically upregulated the levels of Iba-1 and significantly decreased the expression of CD200. IS alone failed to induce cognitive deficits and increase pro-inflammatory cytokines expression. However, IS delayed the recovery of surgery-induced spatial learning and memory impairment and prolonged pro-inflammatory response to the subsequent surgery challenge.
MeSH Terms
- Animals
- Antigens, CD
- Calcium-Binding Proteins
- Cognitive Dysfunction
- Electroshock
- Encephalitis
- Glial Fibrillary Acidic Protein
- Glucocorticoids
- Hippocampus
- Interleukin-1beta
- Interleukin-6
- Male
- Microfilament Proteins
- Postoperative Complications
- Rats
- Rats, Sprague-Dawley
- Recovery of Function
- Spatial Learning
- Stress, Psychological
Keywords
- Aging
- Hippocampus
- Inescapable tailshock (IS)
- Neuroinflammation
- Postoperative cognitive dysfunction (POCD)
- Prior stress
The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) Alzheimer's disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. Neuroimmune regulatory proteins (NIReg) such as CD95L, CD200, CD47, sialic acid, complement regulatory proteins (CD55, CD46, fH, C3a), HMGB1, may control the adverse immune responses in health and diseases. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury as well as an adverse inflammatory response in acute and chronic settings. We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler's virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.
MeSH Terms
- Aging
- Alzheimer Disease
- Antigens, CD
- Antigens, Surface
- Brain
- Encephalitis
- Endocannabinoids
- Humans
- Immunity, Innate
- Multiple Sclerosis
- Orexin Receptors
- Receptors, Cell Surface
CD200 and its receptor, CD200 receptor (CD200R), have uniaue roles in controlling damaging inflammatory processes. At present, the only identified function for CD200 is as a ligand for CD200R. These proteins interact resulting in the activation of anti-inflammatory signaling by CD200R-expressing cells. When this interaction becomes deficient with aging or disease, chronic inflammation occurs, Experimental animal studies have demonstrated the consequences of disrupting CD200-CD200R interactions in the brain, but there have been few studies in human brains. Deficiency in neuronal CD200 may explain the chronic inflammation in human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis; however, deficits in the microglial expression of CD200R may also be of functional significance. The purpose of this review is to assess the data regarding the role of CD200-CD200R interactions in relation to the brain in order to determine if this could be a therapeutic target for human brain diseases with inflammatory components, and what additional studies are needed.
Keywords
- aging
- alternative activation
- anti-inflammatory signaling
- cell surface protein
- endogenous inflammatory regulator
- inflammation
- neurodegenerative disease
- neuropathology
The CD200/CD200R inhibitory immune ligand-receptor system regulates microglial activation/quiescence in adult brain. Here, we investigated CD200/CD200R at different stages of postnatal development, when microglial maturation takes place. We characterized the spatiotemporal, cellular, and quantitative expression pattern of CD200 and CD200R in the developing and adult C57/BL6 mice brain by immunofluorescent labeling and Western blotting. CD200 expression increased from postnatal day 1 (P1) to P5-P7, when maximum levels were found, and decreased to adulthood. CD200 was located surrounding neuronal bodies, and very prominently in cortical layer I, where CD200( ) structures included glial fibrillary acidic protein (GFAP)( ) astrocytes until P7. In the hippocampus, CD200 was mainly observed in the hippocampal fissure, where GFAP( ) /CD200( ) astrocytes were also found until P7. CD200( ) endothelium was seen in the hippocampal fissure and cortical blood vessels, notably from P14, showing maximum vascular CD200 in adults. CD200R( ) cells were a population of ameboid/pseudopodic Iba1( ) microglia/macrophages observed at all ages, but significantly decreasing with increasing age. CD200R( ) /Iba1( ) macrophages were prominent in the pial meninges and ventricle lining, mainly at P1-P5. CD200R( ) /Iba1( ) perivascular macrophages were observed in cortical and hippocampal fissure blood vessels, showing maximum density at P7, but being prominent until adulthood. CD200R( ) /Iba1( ) ameboid microglia in the cingulum at P1-P5 were the only CD200R( ) cells in the nervous tissue. In conclusion, the main sites of CD200/CD200R interaction seem to include the molecular layer and pial surface in neonates and blood vessels from P7 until adulthood, highlighting the possible role of the CD200/CD200R system in microglial development and renewal.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Antibody Specificity
- Antigen-Antibody Reactions
- Antigens, CD
- Brain Chemistry
- Female
- Hippocampus
- Macrophages
- Male
- Membrane Glycoproteins
- Mice
- Mice, Inbred C57BL
- Microglia
- Neocortex
- Neural Inhibition
- Neurogenesis
The glycoprotein, CD200, is primarily expressed on neurons and its cognate receptor CD200R is expressed principally on cells of the myeloid lineage, including microglia. The interaction of CD200 with its receptor plays a significant role in maintaining microglia in a quiescent state and therefore a decrease in CD200 expression in brain is associated with evidence of microglial activation. Conversely, activation of CD200R, for example using a CD200 fusion protein (CD200Fc), should result in a decrease in microglial activation. Here we assessed the effect of delivery of CD200Fc intrahippocampally on microglial activation and on long-term potentiation (LTP) in perforant path-granule cell synapses in young and aged rats. We hypothesized that the age-related changes in microglial activation would be attenuated by CD200Fc resulting in an improved ability of aged rats to sustain LTP. The data indicate that expression of markers of microglial activation including major histocompatibility complex Class II (MHCII) and CD40 mRNA, as well as MHCII immunoreactivity, were increased in hippocampus of aged, compared with young, rats and that these changes were associated with a deficit in LTP; these changes were attenuated in hippocampal tissue prepared from aged rats which received CD200Fc. Microglial activation and a deficit in LTP have also been reported in lipopolysaccharide (LPS)-treated rats and, here, we report that these changes were also attenuated in CD200Fc-treated animals. Thus the negative impact of microglial activation on the ability of aged and LPS-treated rats to sustain LTP is ameliorated when CD200R is activated by CD200Fc.
MeSH Terms
- Actins
- Aging
- Animals
- Antigens, CD
- Blotting, Western
- Chemokines
- Cytokines
- Excitatory Postsynaptic Potentials
- Genes, MHC Class II
- Hippocampus
- Inflammation
- Lipopolysaccharides
- Long-Term Potentiation
- Macrophage Activation
- Male
- Membrane Proteins
- Microglia
- Microinjections
- Neuronal Plasticity
- Rats
- Rats, Wistar
- Real-Time Polymerase Chain Reaction
- Recombinant Fusion Proteins
- Synaptophysin
Altered synaptic morphology, progressive loss of synapses and glial (astrocyte and microglial) cell activation are considered as characteristic hallmarks of aging. Recent evidence suggests that there is a concomitant age-related decrease in expression of the presynaptic protein, synaptophysin, and the neuronal glycoprotein CD200, which, by interacting with its receptor, plays a role in maintaining microglia in a quiescent state. These age-related changes may be indicative of reduced neuroglial support of synapses. FG Loop (FGL) peptide synthesized from the second fibronectin type III module of neural cell adhesion molecule (NCAM), has previously been shown to attenuate age-related glial cell activation, and to 'restore' cognitive function in aged rats. The mechanisms by which FGL exerts these neuroprotective effects remain unclear, but could involve regulation of CD200, modifying glial-synaptic interactions (affecting neuroglial 'support' at synapses), or impacting directly on synaptic function. Light and electron microscopic (EM) analyses were undertaken to investigate whether systemic treatment with FGL (i) alters CD200, synaptophysin (presynaptic) and PSD-95 (postsynaptic) immunohistochemical expression levels, (ii) affects synaptic number, or (iii) exerts any effects on glial-synaptic interactions within young (4 month-old) and aged (22 month-old) rat hippocampus. Treatment with FGL attenuated the age-related loss of synaptophysin immunoreactivity (-ir) within CA3 and hilus (with no major effect on PSD-95-ir), and of CD200-ir specifically in the CA3 region. Ultrastructural morphometric analyses showed that FGL treatment (i) prevented age-related loss in astrocyte-synaptic contacts, (ii) reduced microglia-synaptic contacts in the CA3 stratum radiatum, but (iii) had no effect on the mean number of synapses in this region. These data suggest that FGL mediates its neuroprotective effects by regulating glial-synaptic interaction.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- CA3 Region, Hippocampal
- Disks Large Homolog 4 Protein
- Glial Fibrillary Acidic Protein
- Hippocampus
- Image Processing, Computer-Assisted
- Immunohistochemistry
- Injections, Intraperitoneal
- Intracellular Signaling Peptides and Proteins
- Male
- Membrane Proteins
- Microscopy, Electron
- Neural Cell Adhesion Molecules
- Neuroglia
- Rats
- Rats, Wistar
- Synapses
- Synaptophysin
CD200-CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200-CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200-CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD.
MeSH Terms
- Aging
- Animals
- Antibodies, Blocking
- Antigens, CD
- Cell Culture Techniques
- Cells, Cultured
- Dopamine
- Gene Expression
- Intercellular Adhesion Molecule-1
- Iron
- Mesencephalon
- Microglia
- NADPH Oxidases
- Neurons
- Parkinson Disease
- Polymerase Chain Reaction
- Rats
- Rats, Sprague-Dawley
- Receptors, Immunologic
- Rotenone
- Superoxides
- p38 Mitogen-Activated Protein Kinases
Postoperative cognitive dysfunction (POCD) is characterized by the progressive deterioration of intellectual/cognitive function following surgery. It has been suggested that the senile brain, which characteristically expresses higher levels of central proinflammatory cytokines, interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, is more susceptible to additional insult following surgery. The authors of this study investigated the expression of central cytokines IL-1β, IL-6 and TNF-α and hippocampal glial cell activation in aged and adult rats following partial hepatectomy. Cognitive function was assessed in a reversal-learning version of the Morris water maze (MWM) before and after surgery. Hippocampal pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and glial cell activation markers glial fibrillary acidic protein (GFAP) and S100β were measured at each time point; CD200 and CD200R were also measured to explore potential mechanisms of glial cell activation. Surgical trauma resulted in impairments in distance and latency only on postoperative day 1 (p<0.001, respectively) in adult rats. Aged rats exhibited impairments on day 1 (p<0.001) that persisted until postoperative day 3 (p=0.002 and p=0.001, respectively). All significant impairments paralleled upregulated cytokine IL-1β and IL-6 expression. Immunohistochemistry assay further showed more hippocampal glial cell activation in aged rats compared to that in adults. Overall, these findings suggest that surgical trauma, rather than anesthesia, resulted in cognitive function impairment potentiated by aging. Hippocampal pro-inflammatory cytokines and glial cell activation might mediate trauma-induced POCD.
MeSH Terms
- Aging
- Animals
- Cognition Disorders
- Disease Progression
- Hepatectomy
- Hippocampus
- Inflammation
- Maze Learning
- Neurons
- Postoperative Complications
- Random Allocation
- Rats
- Rats, Sprague-Dawley
Skin hair follicles (HF) contain bulge stem cells (SC) that regenerate HFs during hair cycles, and repair skin epithelia following injury. As natural aging is associated with decreased skin repair capacity in humans, we have investigated the impact of age on human scalp HF bulge cell number and function. Here, we isolated human bulge cells, characterized as CD200 /KRT15 /KRT19 cells of the HF, by dissection-combined CD200 selection in young and aged human skin. Targeted transcriptional profiling indicates that KRT15, KRT19, Dkk3, Dkk4, Tcf3, S100A4, Gas1, EGFR and CTGF/CCN2 are also preferentially expressed by human bulge cells, compared to differentiated HF keratinocytes (KC). Our results demonstrate that aging does not alter expression or localization of these HF SC markers. In addition, we could not detect significant differences in HF density or bulge cell number between young and aged human scalp skin. Interestingly, hedgehog (Hh) signaling is activated in human bulge cells in vivo, and down-regulated in differentiated HF KCs, both in young and aged skin. In addition, activation of Hh signaling by lentivirus-mediated overexpression of transcription factor Gli1 induces transcription of HF SC markers KRT15, KRT19, and Gas1, in cultured KCs. Together with previously reported knock-out mouse results, these data suggest a role for Hh signaling in maintaining bulge cell phenotype in young and aged human skin.
MeSH Terms
- Adult
- Aged
- Aging
- Antigens, CD
- Cell Cycle Proteins
- Cell Separation
- GPI-Linked Proteins
- Hair Follicle
- Hedgehog Proteins
- Humans
- Keratin-15
- Keratinocytes
- Membrane Proteins
- Stem Cells
A common change that occurs with age in the central nervous system is an increase in microglial-associated inflammation. This is usually coupled with an increase in the concentration of the inflammatory cytokine interleukin-1beta (IL-1beta) in the hippocampus and an inhibition in long-term potentiation. To assess the effects of a novel preparation of phospholipid nanoparticles incorporating phosphatidylglycerol, VP025, on inflammatory changes in hippocampus of aged and lipopolysaccharide (LPS)-treated rats. We report that a possible initial target cell of the putative anti-inflammatory actions of VP025 may be macrophages, as VP025 is engulfed by, and has the capacity to alter the activity of, these cells. VP025 reversed the increase in IFN-gamma concentration in supernatant taken from peritoneal macrophages harvested from LPS-treated rats. In addition, markers of microglial activity, major histocompatibility complex class II (MHC II) mRNA expression, CD40 expression and IL-1beta concentration were increased, and CD200 expression was reduced, in the hippocampus of these rats. VP025 reversed changes in CD40, IL-1beta and CD200 in aged rats, and also restored long-term potentiation in aged and LPS-treated rats. We conclude that VP025 has the ability to modulate the activity of macrophage, microglia and neurons in response to stressors such as ageing and LPS treatment.
MeSH Terms
- Adult
- Aging
- Animals
- Anti-Inflammatory Agents
- Encephalitis
- Gliosis
- Hippocampus
- Humans
- Immunomodulation
- Interferon-gamma
- Interleukin-1beta
- Long-Term Potentiation
- Macrophages
- Male
- Memory Disorders
- Microglia
- Nanoparticles
- Perforant Pathway
- Phagocytosis
- Phosphatidylglycerols
- Phospholipids
- Rats
- Rats, Wistar
- Tumor Cells, Cultured
- Tumor Necrosis Factor-alpha
In normal brain aging, CNS resident macrophages exhibit increased expression of major histocompatibility complex (MHC) II expression. However, the transcriptional basis for this observation has not been clarified nor have age-related alterations in pivotal pro-inflammatory genes been characterized. Age-related mRNA alterations in MHC II, MHC II accessory molecules and several pro-inflammatory mediators were measured in older (24 months) and younger (3 months) male F344xBN F1 rats. Real time RT-PCR was utilized to measure steady state mRNA levels in hippocampus. Older as compared to younger animals exhibited increased mRNA levels of MHC II, CD86, CIITA and IFN-gamma. Furthermore, IL-10 and CD200 mRNA, molecules that down-regulate macrophage activation, was decreased in older animals. The present results indicate that normal brain aging is characterized by a shift towards a pro-inflammatory microenvironment in the CNS.
MeSH Terms
- Aging
- Animals
- Antigens, CD
- Brain
- DNA Primers
- DNA, Complementary
- Gene Expression Regulation, Developmental
- Genes, MHC Class II
- Inflammation
- Male
- Neurons
- RNA, Messenger
- Rats
- Rats, Inbred F344
- Receptors, Immunologic
- Reverse Transcriptase Polymerase Chain Reaction
- Up-Regulation