Review Article CD200-CD200R Signaling and Diseases: a Potential Therapeutic Target?

Int J Physiol Pathophysiol Pharmacol 2019;11(6):297-309 www.ijppp.org /ISSN:1944-8171/IJPPP0105962

Review Article CD200-CD200R signaling and diseases: a potential therapeutic target?

Conelius Ngwa, Fudong Liu

Department of Neurology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA Received December 5, 2019; Accepted December 13, 2019; Epub December 15, 2019; Published December 30, 2019

Abstract: CD200 and its receptor, CD200R, constitutes an endogenous inhibitory signaling, and is being increasingly recognized in studies of various central nervous system (CNS) disorders. Emerging data have demonstrated that neuronal CD200 binds to CD200R to modulate immune responses to pathogenic stimuli. However, on which component of the immune response that CD200-CD200R signaling acts is not well understood. In this review, we focused on cellular expression of the signaling, the effects on immune cell activation, and the function in pathological procedures of neurodegenerative diseases, in both clinical and experimental disease models. Essential functions of CD200-CD200R interaction and the treatment relevance have been elaborated. Immune responses to diseases under the control of CD200-CD200R axis were also discussed in the review.

Keywords: Brain, CD200, CD200R, immune responses, neuron

Introduction is mainly expressed by myeloid cells [20, 26, 30], but also present on thymocytes [15], T and Immune responses to brain tissue damage are B cells [8, 24]. CD200R family include CD200- triggered by the recognition of non-self or R1, R2, R3 and R4 in mouse; and CD200R1 altered self-molecular patterns by professional and R2 in human [31, 32]. However, it was cells including microglia, neurons, astrocytes, found that CD200 only binds to CD200R1 but and oligodendrocytes [1, 2]. The recognition is not the ligand for other CD200R isoforms leads to activation of immune cells that is regu- [16, 17]. CD200R interacts with CD200 ligand lated by endogenous inhibitory pathways inclu- through its N-terminal Ig V-type domain, form- ding CD200 signaling. The cluster of Diffe- ing an endogenous inhibitory signaling for im- rentiation-200 (CD200), a 41-47 KDa protein mune responses [18]. The human CD200R ge- [3-11] characterized by two immunoglobulins ne spans a region of 52 kb consisting of nine superfamily (IgSF) domains [11], one trans- exons and encodes a 348-amino-acid cell-sur- membrane region, and a small cytoplasmic face protein [14]. In contrast to murine CD200R domain, is suggested to be devoid of intracel- protein, the human membrane-bound and solu- lular signaling function [12]. However, primarily ble CD200R proteins have an insertion of 23 expressed in the somas, axons, dendrites and amino acids at position 23, encoded by exon 2, synapses of neurons, and in endothelial cells, which generates a putative dihydroxyacid dehy- CD200 is an important inhibitory ligand to inter- dratase domain [14]. Despite these differenc- act with immune cells [10]. Genes encoding es, CD200-CD200R signaling plays a pivotal CD200 are located on chromosome 3, precise- role in modulating immune responses in both ly 3q12-13. The homology between human and murine and human upon inflammatory stimuli. mouse CD200 is 77.6% for protein and 81.7% for DNA, which in the case of human vs. rat is Molecular mechanisms of CD200-CD200R 77.2% (protein) and 80.7% (DNA) [13]. CD200 signaling receptor (CD200R) also has two IgSF domains but with a longer cytoplasmic tail [7, 21], consti- CD200R does not contain any immunoreceptor tuting a cellular signaling domain [14]. CD200R tyrosine-based inhibitory motifs (ITIMs) which CD200-CD200R signaling and disease

Figure 1. Presumptive mechanism of CD200-CD200R interactions underlying the activation of immune cells (mono- cytes, lymphocytes, etc.). The primary mechanism involves activation of Dok2 and RasGAP, leading to the inhibition of Ras activation and suppression of downstream effects on PI3K and Erk. Resultantly an increase of multiple anti- inflammatory signals occurs due to the inhibition of NF-kB. Activation of RasGAP can be inhibited by the combination of Dok1 and CrkL, leading to activation of NF-kB and the pro-inflammatory phenotype. pY: Phosphotyrosine. This illustration is based on the findings from [7, 22, 29, 69, 85, 86]. are usually present in a large number of inhibi- RAS p21 protein activator (RasGAP) which is an tory receptors and which mediate their inhibi- SH2 domain containing protein [21, 22]. The tory roles through the recruitment of protein formation of the Dok2-RasGAP complex inhibits tyrosine phosphatases such as Src homology 2 Ras activation (Figure 1), leading to inhibition domain-containing phosphatase (SHP) 1, SH2, of other downstream inflammatory signals th- or the inositol phosphatase (SHIP) upon phos- rough inhibition of principal mitogen activated phorylation [19]. Instead, the molecular signal- protein kinases including Phosphoinositide 3- ing mechanism of CD200R following activation kinase (PI3K) and Extracellular Signal-regulated involves direct interaction of the adaptor pro- Kinase (Erk) [10, 23-25]. According to Snelgrove tein downstream to tyrosine kinase (Dok2), et al. [26] the interaction between CD200 and with the membrane distal tyrosine residue lo- CD200R induces phosphorylation of tyrosine cated within a phosphotyrosine-binding (PTB) residues, initiating a signaling cascade which domain recognition motif (NPxY) [20]. This in- recruits SHIP and RasGAP [27, 28]. Dok2 ap- teraction leads to binding and recruitment of pears to be regulated by Dok1 through Crk Like

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(CrkL)-RasGAP suppression; both Dok2 and mune cells in mouse brains subjected to ex- Dok1 are recruited during CD200-CD200R in- perimental ischemic stroke model, and found teraction that leads to recruitment of RasGAP microglia express near null CD200R; while and SH2-containing inositol phosphatase [29]. robust signals of the receptor were found in As shown in Figure 1, Dok1 activation is ini- lymphocytes with modest expression on mo- tiated through binding to one of the three ph- nocytes [39]. The vast amount of infiltrating osphotyrosine residues located on the cyto- CD200R+ leukocytes in the ischemic brain in- plasmic amino acid chain of CD200R. This dicates the enhanced activation of these im- Dok1-phosphotyrosine binding then suppress- mune cells, which could be attributed to the es Dok2’s effect on Ras through activation of loss of neuronal CD200 after stroke. CrkL [30]. It has been demonstrated that knockdown of Dok2 but not Dok1 ameliora- CD200R may not be the sole receptor for neu- ted the increase in IL-8 production following ronal CD200. The addition of CD200 to primary CD200R activation in U937 cells [29]. The regu- neuronal cultures promoted neuronal survival latory effect of Dok2 by Dok1 was also con- and neurogenesis, an experiment performed firmed by using macrophages with Dok1 kno- through CD200 binding to the fibroblast grow- ckdown, which shows increased phosphoryla- th factor receptor (FGFR) instead of CD200R1 tion of Dok2 and enhanced recruitment of [40]. Since the ultimate anti-inflammatory ef- RasGAP [14]. Thus, the activation and recruit- fect of FGFR activation was suggested being ment of Dok2, and the subsequent activation mediated by CD200 upregulation [28, 29], fur- of RasGAP are the key events downstream to ther research is warranted to investigate whe- the CD200-CD200R interaction that induce ther the protective effects of neuronal CD200 immune regulatory function in immune cells are derived from either a direct interaction with [29]. CD200R on immune cells or indirectly by bind- Neuronal CD200 signaling ing to other putative receptors.

CD200 is mainly expressed by neurons and CD200 signaling with aging vascular endothelia cells [31-33], although rel- CD200 levels in neurons reduce with age [41, atively weaker expression was also found in astrocytes and oligodendrocytes [12, 25, 36], 42]. Frank and his collaborators [41] compar- as well as in peripheral thymocytes [3, 24] and ed the gene-expression profiles of the hippo- NK cells [34]. Neurons express the highest campus from young (3 months) and aged (24 level of CD200 compared to other cell types months) male F344xBN F1 rats. Their data [35], and execute their functions on immune showed a decrease in CD200 mRNA in the cells where CD200 receptor (CD200R) is ex- older animals accompanied by a significant pressed, including macrophages and dendritic increase in mRNA levels of inflammatory ma- cells [39, 49], B and T cells [39, 45]. CD200 rkers including the major histocompatibility gene in the human brain is likely regulated dif- complex (MHCII), Cluster of Differentiation-86 ferently compared with rodents [13]; however (CD86), and interferon gamma (IFN-γ). Micro- the characterization of human CD200 localiza- glial activation in the hippocampus of aged and tion [14, 15] has shown a similar distribution on β-amyloid (Aβ)-treated rats was accompanied neuronal cell membrane as that of rodents [13, by decreased expression of neuronal CD200, 35]. Microglial CD200R expression has been providing evidence that neurons can downre- controversial, as low levels of CD200R have gulate the microglial activation through CD200 been detected in microglia from multiple scle- signaling [43]. Data from this report also show- rosis [35] and Alzheimer’s disease (AD) [36] ed that the expression of CD200 was increased animal models. In another report CD200R was by IL-4 supplement, suggesting that IL-4 is also only present in macrophages but not microglia involved in the neuronal CD200 signaling to [37, 38]. In vitro studies showed that isolated downregulate the activation of aged microglia microglia from AD human brains had low levels under inflammatory conditions. of CD200R mRNA and protein compared with that in blood-isolated macrophages [36], sug- With the aim of characterizing CD200 and gesting that monocytic cells are more sensitive CD200R expression in elderly human brains, to CD200-CD200R signaling. Our recent study Walker et al. [13] found that many neurons examined CD200R expression in infiltrating im- in the cortex and hippocampus did not show

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CD200 immunoreactivity. Quantitative studies tration in the brain, greater spontaneous bacte- on human AD brain tissues from averagely rial colonization of the lung, and worse stroke 84.4 year old patients (16 females and 15 outcomes [39]. CD200R may also co-exist with males) showed a significant decrease in CD200 CD200 in immune cells and functions through protein and mRNA in the hippocampus and an autocrine mechanism. Using rat MCAO mo- inferior temporal gyrus, but not in the cerebel- del, Matsumoto et al. [11] found that macro- lum [34]. A significant decrease in CD200R phage-like cells expressing CD200 have sup- mRNA expression in AD hippocampus and infe- pressive effects on activation of myeloid cells rior temporal gyrus, but not in cerebellum, was including microglia by interacting with CD200R. also detected. Low expression of CD200R by In this study CD200-mRNA and protein were microglia was confirmed at the mRNA and pro- detected in the ischemic core as well as the tein level using cultured human microglia com- contralateral region, and in isolated spherical pared to blood-derived macrophages [34], and Iba1+ macrophage-like cells. Similarly, it was the treatment of cultured microglia and macro- reported that microglial CD200 interacts with phages with IL-4 and IL-13 significantly incre- CD200R to maintain microglia in an alternative- ased the expression of CD200R. These data ly activated state, whereas interactions betwe- indicate that the CD200-CD200R axis may be en neuronal CD200 and microglial CD200R deficient in AD brains and mechanisms aimed keep microglial quiescent [51]. at increasing levels of CD200 and CD200R could be neuroprotective in human neurode- Interestingly, physical exercise and stem cell generative diseases. treatment have been found to boost the CD200-CD200R signaling in experimental str- Ischemic stroke oke studies. Sun et al. [52] found that treadmill exercise significantly increased CD200 and Ischemic stroke, the leading cause of death CD200R levels in the ipsilateral hippocampus and long-term disability in the USA [44, 45], and cortex, and facilitated sensorimotor cogni- accounts for > 80% of all stroke cases [46]. tive functional recovery after tMCAO. In addi- Post-stroke inflammation is a fundamental tion, neural stem/progenitor cell proliferation, pathophysiological process that is tightly con- differentiation, and migration were enhanced trolled by endogenous regulatory pathways in- in the ipsilateral subventricular and subgranu- cluding CD200-CD200R signaling. In the acute lar zones. Human placenta amniotic membr- phase of brain ischemia, neuronal CD200 ex- ane-derived mesenchymal stem cells (AMSCs) pression is markedly decreased in the brain transplanted into ischemic rat brains dramati- due to the degeneration of CD200-expressing cally inhibited the expression of pro-inflamma- cells [11, 47]; however, increased expression of tory cytokines and increased CD200 expres- CD200 was found 5 days after stroke [11, 47, sion in neurons, as compared with the sham- 48]. It was suggested that this unstable ex- treated group [53]. The reason why stem cells pression during ischemia disrupts the CD200- promote CD200-CD200R signaling in stroke is CD200R axis and triggers microglial activation not known, which might be delivered by the [49]. Yang et al. [50] reported that the expres- intrinsic protective mechanism conveyed by the sion of CD200 was decreased within 48 h after new-born cells. permanent middle cerebral artery occlusion (pMCAO) accompanied by a decrease of neu- Alzheimer’s disease ron-specific enolase (NSE) expression. The loss of CD200 caused by neuronal death could be Alzheimer’s disease (AD) is morphologically dis- one of contributing factors in immune cell acti- tinguished by the presence of senile plaques vation after cerebral ischemia. in the brain, composed mainly of different spe- cies of fibrillar amyloid-β (Aβ) produced by the We have found that CD200-CD200R inhibitory cleavage of the Aβ precursor protein (APP), and axis could be a critical regulator of peripheral neurofibrillary tangles composed of various iso- immune response after brain ischemia, impact- forms of hyperphosphorylated and truncated ing animal survival rate and their susceptibility tau proteins [54-57]. CD200 levels have been to post-stroke infection, as the loss of CD200R found decreased in AD brains mainly in hippo- signaling leads to exacerbated leukocyte infil- campus and inferior temporal gyrus [36, 58].

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Data obtained from brain tissues of AD patients injection. Decreased CD200 mRNA expression showed that there is not only a deficit of CD200 has been reported in the rim and center of MS but also of CD200R [36]. It has been estab- lesions, as well as in adjacent normal white lished that aggregated Aβ plaques activates matter compared with matched controls [66]. microglia to a pro-inflammatory state, augment- ing phagocytic and lysosomal activity, and In both EAE and experimental autoimmune capable of producing a wide range of neurotox- uveoretinitis (EAU) mice with CD200 deficiency, ic mediators [43, 58, 69, 70]. Lyons et al. [59] variations in peripheral immune cell infiltration examined the impact of CD200 deficiency on were observed. The infiltration of monocyte-de- Aβ-induced changes in microglia and reported rived macrophages is increased after EAU or that the effect of Aβ was surprisingly reduced in EAE induction [67-69], and blockade of CD200R microglia prepared from the CD200-deficient leads to an increase in T-lymphocyte and mono- mice. It was previously shown that CD200FC cyte-derived macrophage infiltration in both administration reduced pro-inflammatory cyto- models [70-72]. Interestingly, the increase in kine production in the presence of Aβ in microg- these monocyte-derived macrophages and lia and attenuated the decrease in long-term T-lymphocyte were reversed following adminis- potentiation (LTP) [60]. In summary, these data tration of CD200-Fc [65, 70]. The involvement clearly showed that CD200-CD200R signaling of CD200-CD200R in immune cell infiltration is critical for Aβ removal and could be associ- could be related to the expression of CD200 in ated with other intrinsic molecules, and proba- capillary endothelial cells as immune regulato- bly related to microglial phagocytosis. ry agents [73-75]. Another explanation is that T-cell infiltration may be favored by an enhanced Parkinson’s disease microglial activation state, as already shown in CD200-deficient mice, due to the release of an In one study using Parkinson’s disease (PD) increased number of chemokines, including model created in rodents by 6-hydroxydopa- CCL-2, CCL-5, or CXCL-10 [74]. These reports mine injection into substantia nigra (SN) neu- reinforced the rational that CD200-CD200R is rons, blocking of CD200R resulted in signifi- an important immunoregulatory signaling in cantly more severe PD-like movement dysfunc- autoimmunity, and suggested that targeting tion and a significantly greater loss of tyrosine hydroxylase-positive dopaminergic neurons in CD200-CD200R can dampen neuroinflamma- SN [37]. A 4-fold greater number of activated tion and demyelination, and halt the progres- microglia was noticed in rats treated with sion of MS. CD200R blocking antibody compared with con- CD200-CD200R signaling in other diseases trol animals, accompanied by 3 to 4-fold higher levels of TNF-α and IL-6 in the SN. Blocking Tumorigenesis: A number of groups have con- CD200-CD200R interaction by anti-CD200R firmed that high expression of CD200 in tu- antibody resulting in microglial activation and mor cells is an independent prognostic factor intensified neurodegeneration in PD was also predicting reduced overall survival rate in a confirmed in monocyte-derived macrophages number of hematological malignancies includ- (MDMs) from 32 individuals with advanced PD ing multiple myeloma, acute myeloid leukemia [61], demonstrating an essential role of this (AML), and chronic lymphocytic leukemia (CLL) CD200-CD200R axis in the regulation of PD. [76-78]. How CD200 signaling suppresses anti- Multiple sclerosis tumor responses remains elusive although the malignity of CD200-expressing tumors may Data of CD200 signaling in multiple sclero- suggest a direct inhibitory signal delivered by sis (MS) have been mainly from studies with the tumor against the anti-tumor response [79]. Experimental Autoimmune Encephalomyelitis Bisgin et al. [80] examined the immunohistoch- (EAE) which showed disruption of CD200- emical expression and localization of CD200 CD200R interaction due to neuronal damage and CD200R1 in rectal cancer patients; the re- leading to microglia activation [62-65]. Accor- sults showed a strikingly high level of CD200 ding to Lyons et al. [59], both the severity and in tumor cells and high CD200R1 expression in disease progression during the chronic phase normal mucosal epithelium and stromal cells. of EAE in mice were ameliorated by CD200-Fc Kawasaki et al. [81] hypothesized that cancer

301 Int J Physiol Pathophysiol Pharmacol 2019;11(6):297-309 CD200-CD200R signaling and disease stem cells might be able to evade the immune orders of magnitude lower than that of CD200 system by generating a tolerogenic response [13, 36]; therefore, boosting CD200R may be facilitated by CD200. CD200 expression incre- more effective especially in diseases where the ases on a breast cancer cell line transplanted CD200R levels remain low. to immune competent mice in contrast to immune deficient mice [82], suggesting a CD200 Cannabinoids participate in the control of brain mediated anti-inflammatory profile of CD200 immune responses as well as in the protection positive cancer cells. In a word, CD200 signal- of the CNS against injury [88-92]. Treatments ing seems to benefit cancer by diminishing with the endocannabinoid compound N-arachi- immune responses. donoylethanolamine (AEA) induced the recovery of CD200 and CD200R gene expression Allergy: Mast cells and basophils play a crucial that was reduced in the Theiler’s murine en- role in allergic reactions in body tissues and cephalomyelitis virus induced demyelinating blood respectively. It has been confirmed that disease (TMEV-IDD) model of MS [85]. This was CD200-CD200R interaction reduces their de- accompanied by decreased inflammatory medi- granulation and attenuates the allergic inflam- ators and reduced microglial reactivity. Endo- mation [12, 27]. Administration of intratrach- cannabinoids may regulate CD200-CD200R eal CD200 recombinant to experimental asth- axis through activating cannabinoid receptors matic rats was reported to inhibit airway hyper- expressed on immune cells including microglia, responsiveness by local alterations of T cell astrocytes, and neurons [91-94]. The endoge- response and cytokine secretion [83]. nous ligand 2-arachidonoylglycerol (2-AG) binds and activates cannabinoid 2 (CB2) receptor CD200-CD200R signaling as a therapeutic [91, 95]. Neurons and glial cells produce 2-AG target [96-99] suggesting CB2 receptors and 2-AG could play a role in the regulation of the CD200- The therapeutic potential of CD200 has been CD200R axis especially in diseases where CB2 explored both in vitro and in vivo. Studies using receptors are more likely to be expressed by neuron-microglia co-cultures suggested that immune cells. CD200-CD200R interaction may be one of the mechanisms by which IL-10 protects neurons Studies of manipulation of the CD200-CD200R from inflammatory damage caused by microg- axis have tested the effect of anti-CD200 mo- lia-induced cytotoxicity, as IL-10 increased the noclonal antibodies, and also soluble CD200R expression of CD200 in neurons [58, 84, 85]. or fragments of CD200 [39, 71, 100]. A thera- An up-regulatory effect of IL-4 on CD200 ex- peutic trial based on the use of CD200 block- pression has also been reported [43, 86]. IL-4- ing antibodies in chronic lymphocytic leukemia deficient mice showed low expression of CD200 (CLL) patients with ClinicalTrials.gov Identifier in neurons, but IL-4 intracerebroventricular ad- NCT00648739 [101] has recently been con- ministration was able to reverse CD200 expres- ducted. Of the 23 patients with advanced CLL sion to normal levels [86]. Likewise, adeno enrolled, 21 patients received > 1 treatment associated viral gene-delivery of IL-4 in APP- cycle with samalizumab, a novel recombinant PS1 mice restored CD200 expression in the humanized monoclonal antibody that targets hippocampus [84, 87], and treatment of cul- CD200. Treatment produced dose-dependent tured microglia from aged rodents with IL-4 decreases in CD200 expression on CLL cells resulted in the production of CD200 [13, 51]. and decreased turnover of circulating CD200+ These data indicate that it is feasible to manip- CD4+ T cells. This first-in-human investigation ulate CD200-CD200R signaling. showed a good and safe treatment protocol that was associated with reduced tumor bur- In AD brains, microglia are primarily classically den in a majority of patients [101], and sup- activated but enhancing CD200R expression port further development of samalizumab ther- can promote alternative activation to confer apy for immune responses. Targeting CD200- neuroprotection. Up to date, it is not known yet CD200R signaling to modulate the immune how much of CD200 expression is sufficient to response represents a promising therapeutic activate CD200R. In human brains the level strategy for various inflammatory diseases. of CD200R expression appears to be several Table 1 summarizes commonly used animal

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Table 1. Summary of experimental CD200-CD200R axis Disease Animal model Tissue Function of CD200 signaling Intervention of CD200-CD200R signaling Ref. Ischemic stroke CD-1 mice Cortex Restored neural progenitor cell proliferation, differentiation, Intracerebroventricular injection of recombinant CD200 protein [50] and migration. after pMCAO. Decrease of Iba-1, IL-1β, TNF-α, and IL-10. Sprague-Dawley rats Ipsilateral hippocampus Sequential treadmill exercise for 4 weeks, with different speed [52] and cortex and running times. Alzheimer’s APP-PS1 mice Hippocampus Restored neural progenitor cell proliferation and AAV2/1-CD200 bilateral injection into the CA1 region of hip- [84] differentiation in the subgranular and granular cell layers of pocampus at 6 months of age. + dentate gyrus and reduce diffuse but not thioflavin-s plaques. AAV-IL-4 bilateral injection into mouse hippocampus at 3 [87] months of age. Parkinson’s Sprague-Dawley rats Substantia nigra Function loss due to depletion of dopaminergic neurons and Injection into the right striatum with CD200R-blocking antibody, [37] decrease in tyrosine hydroxylase-immunoreactive neurons. and then with 6-hydroxydopamine the next day injected unilaterally into the right ascending medial forebrain bundle. EAE C57BL/6 mice Spinal cord Attenuated the course of EAE and decreases axonal loss and Subcutaneous administration of CD200-Fc from onset of EAE [65] demyelination. to day 30. GL261 glioma tumors C57BL/6 mice Brain Negatively regulated immune response by activating CD200R Intradermal injection with CD200R antagonist peptide. [105] on myeloid-derived suppressor cells promoting tumorigenesis.

303 Int J Physiol Pathophysiol Pharmacol 2019;11(6):297-309 CD200-CD200R signaling and disease models for CD200 signaling study in neuroin- repair: the role of microglia, astrocytes, “pro- flammatory diseases. tective” glial stem cells and stromal ependy- mal cells. Brain Res Brain Res Rev 2005; 48: Summary 220-233. [3] Barclay AN and Ward HA. Purification and The neurobiological roles of CD200-CD200R chemical characterisation of membrane glyco- signaling in CNS disorders have not been well proteins from rat thymocytes and brain, recog- understood. Probably owing to the differences nised by monoclonal antibody MRC OX 2. Eur J between rodents and humans in the expres- Biochem 1982; 129: 447-458. sion of CD200 and CD200R, data from litera- [4] McMaster WR and Williams AF. Monoclonal ture about the pathway have been controver- antibodies to Ia antigens from rat thymus: cross reactions with mouse and human and sial. The development of humanized transgenic use in purification of rat Ia glycoproteins. Im- mice that express the human genes under their munol Rev 1979; 47: 117-137. native promoters have been reported [102- [5] Barclay AN, Clark MJ and McCaughan GW. 104], which appears to be promising in the Neuronal/lymphoid membrane glycoprotein research of the field. As most of the experimen- MRC OX-2 is a member of the immunoglobulin tal studies have involved application of CD200 superfamily with a light-chain-like structure. protein or CD200R-blocking antibodies, an ap- Biochem Soc Symp 1986; 51: 149-157. proach that has been questioned for human [6] Clark MJ, Gagnon J, Williams AF and Barclay therapy, the development of suitable gene vec- AN. MRC OX-2 antigen: a lymphoid/neuronal tors that can target at neural cells, or embry- membrane glycoprotein with a structure like a onic stem cells could be more relevant. The single immunoglobulin light chain. EMBO J research of CD200-CD200R signaling in ne- 1985; 4: 113-118. uroinflammatory diseases, including ischemic [7] Barclay AN, Wright GJ, Brooke G and Brown stroke, is still in its infancy; further studies at MH. CD200 and membrane protein interactions in the control of myeloid cells. Trends Im- both the cellular and molecular levels are war- munol 2002; 23: 285-290. ranted to better understand the inhibitory [8] Wright GJ, Jones M, Puklavec MJ, Brown MH signaling. and Barclay AN. The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) Acknowledgements glycoprotein is conserved in humans. Immu- nology 2001; 102: 173-179. This work was supported by funding from Na- [9] Slepko N and Levi G. Progressive activation of tional Institutes of Health: R01 NS093042/ adult microglial cells in vitro. Glia 1996; 16: NS108779 (Fudong Liu). 241-246. [10] Manich G, Recasens M, Valente T, Almolda B, Disclosure of conflict of interest Gonzalez B and Castellano B. Role of the CD200-CD200R axis during homeostasis and None. neuroinflammation. Neuroscience 2019; 405: 118-136. Address correspondence to: Dr. Fudong Liu, De- [11] Matsumoto H, Kumon Y, Watanabe H, Ohnishi partment of Neurology, The University of Texas T, Takahashi H, Imai Y and Tanaka J. Expres- Health Science Center at Houston McGovern Me- sion of CD200 by macrophage-like cells in dical School, 6431 Fannin Street, Houston, TX ischemic core of rat brain after transient mid- 77030, USA. Tel: 713-500-7038; Fax: 713-500- dle cerebral artery occlusion. Neurosci Lett 0660; E-mail: [email protected] 2007; 418: 44-48. [12] Holmannova D, Kolackova M, Kondelkova K, References Kunes P, Krejsek J and Ctirad A. CD200/ CD200R paired potent inhibitory molecules [1] Elward K and Gasque P. “Eat me” and “don’t regulating immune and inflammatory respons- eat me” signals govern the innate immune re- es; Part II: CD200/CD200R potential clinical sponse and tissue repair in the CNS: emphasis applications. Acta Medica (Hradec Kralove) on the critical role of the complement system. 2012; 55: 59-65. Mol Immunol 2003; 40: 85-94. [13] Walker DG and Lue LF. Understanding the neu- [2] Hauwel M, Furon E, Canova C, Griffiths M, Neal robiology of CD200 and the CD200 receptor: a J and Gasque P. Innate (inherent) control of therapeutic target for controlling inflammation brain infection, brain inflammation and brain in human brains? Future Neurol 2013; 8.

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