Decreased expression of CD200 and CD200 receptor in Alzheimer's disease: A potential mechanism leading to chronic inflammation
Introduction
The role of inflammation in contributing to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) has been intensively studied since the identification of prominent responses by microglia (brain resident macrophages) to degenerative structures in brain tissues affected by these diseases (Neuroinflammation Working Group, 2000, Hirsch et al., 2003). Pathological studies of AD indicated that the presence of activated microglia, reactive astrocytes, and complement activation, particularly in association with amyloid beta (Aβ)-containing plaques, demonstrated that a type of chronic inflammation was ongoing (McGeer and McGeer, 2003, Xiang et al., 2006, Sastre et al., 2006). A range of in vitro studies using cultured microglia from humans or rodents demonstrated that aggregated Aβ peptide could activate microglia to a proinflammatory state (Walker et al., 2006, Chen et al., 2005, Combs et al., 2001, Giulian et al., 1998, Gan et al., 2004, Yan et al., 1996). As activated microglia have the potential to produce a wide range of neurotoxic molecules, it was hoped that anti-inflammatory therapies might provide new targets for treating this disease (Launer, 2003, MacKenzie and Munoz, 1998, McGeer et al., 1996). Similarly, pronounced microglial responses were observed in the substantia nigra of PD patients, again establishing a neuroinflammatory component to this disease (Hirsch et al., 2003, McGeer et al., 1988bMcGeer et al., 1988a, Teismann et al., 2003). Since clinical trials with anti-inflammatory agents did not generally show effectiveness at slowing the progression of AD, other inflammatory therapeutic targets need to be considered. These targets can include enhancing the function of endogenous immune regulatory molecules. One such immunoregulatory system involves CD200 and CD200 receptor (CD200R). CD200 is a type-1 membrane glycoprotein of the immunoglobulin superfamily (IgSF) of cell surface proteins. It contains 2 IgSF domains and is expressed in a variety of lymphoid and non-lymphoid cells, including kidney glomeruli, vascular endothelium, and subsets of neurons. It was shown that CD200 was expressed by various populations of neurons in rodent brains (Barclay et al., 2002, Wright et al., 2001), but its neuroanatomy and biochemistry in human brain, and involvement in human neurodegenerative diseases such as AD, has not been studied extensively. CD200 (previously known as OX2) was studied for a number of years before being identified as the ligand for a myeloid cell receptor that became designated CD200 receptor (CD200R) (Wright et al., 2003, Wright et al., 2000). CD200R is a closely related molecule to CD200, also having two IgSF domains (Vieites et al., 2003), and is primarily expressed by myeloid cells (e.g. macrophages, neutrophils, monocytes and microglia) (Gorczynski et al., 2004, Voehringer et al., 2004, Vieites et al., 2003, Hatherley and Barclay, 2004). CD200R is a highly glycosylated protein with a molecular weight ranging from 60 to 110 kDa depending on the degree of glycosylation and expressing cell type; four separate CD200R-related genes have been identified in humans (Wright et al., 2003).
There is a growing body of data on the significance of CD200/CD200R in modulating tissue inflammation in various inflammatory diseases (Barclay et al., 2002, Elward and Gasque, 2003, Gorczynski et al., 2002a, Gorczynski et al., 2002b). Their interaction is also involved in inducing immune tolerance, and the prevention of tissue rejection (Clark et al., 2003, Rosenblum et al., 2004). In addition, increased expression of CD200 has been demonstrated in a number of cancers (Kretz-Rommel et al., 2007, Moreaux et al., 2008, Siva et al., 2008). For example, increased expression of CD200 in melanoma cells correlated with their metastatic potential, similarly CD200 expression by multiple myelomas correlated with the survival outcome of patients (Petermann et al., 2007, Siva et al., 2008, Moreaux et al., 2006). Increased CD200 expression appears to enhance the ability of cancer cells to escape immunological removal. CD200 has many features of related cell adhesion molecules; however, there is no evidence that it can activate intracellular signaling pathways. It has been shown that an interaction between the extracellular domains of CD200 and CD200R is necessary for the activation of anti-inflammatory signals by CD200R (Chen and Gorczynski, 2005, Hatherley and Barclay, 2004). Activation of the ERK, JNK, and p38 mitogen activated protein kinase (MAPK) pathways was inhibited by CD200R engagement with CD200 (Zhang et al., 2004). It has been demonstrated that responsiveness to CD200 was dependent on the level of expression of CD200R (Jenmalm et al., 2006). Monocytic cell lines that expressed high, medium, low or very low amounts of CD200R were treated with CD200 and then challenged with interferon-γ (IFN-γ). The low and very low CD200R-expressing cells showed minimal inhibitory response to CD200, measured as reduction in secretion of interleukin (IL)-8, unless CD200R was further crosslinked by antibody, while cells expressing medium to high levels of CD200R showed significant inhibitory response to applied CD200 (Jenmalm et al., 2006).
The significance of CD200/CD200R interactions has been demonstrated from a number of animal studies. One study showed a decrease in CD200 mRNA expression in the hippocampus of rats with increasing age (Frank et al., 2006). Another study showed that mice lacking the CD200 gene had significantly greater numbers of activated monocytes/macrophages under constitutive conditions, and macrophage/microglial activation and inflammatory damage were exacerbated in these animals following injurious treatments (e.g. collagen-induced arthritis, facial nerve transaction, induction of experimental allergic encephalomyelitis (EAE)) (Hoek et al., 2000). Similarly, mice lacking CD200R1 expression showed enhanced tumor necrosis factor-α production in response to lipopolysaccharide, and a lack of ability by CD200 to suppress this inflammatory response (Boudakov et al., 2007). It was recently shown that the reduced susceptibility to EAE by the wld mutant mouse strain was due to enhanced neuronal expression of CD200, which aided in suppression of CNS inflammation (Chitnis et al., 2007). Blocking CD200 in wld mice with antibodies restored EAE pathology to control levels. In mice treated to develop experimental autoimmune uveoretinitis, both CD200 knockout mice and wild type mice treated with antibody to block CD200–CD200R interactions had enhanced inflammation and tissue damage compared to controls. By comparison, in the same model, wild type mice treated with CD200R agonist antibodies showed less tissue damage and inflammation (Banerjee and Dick, 2004, Copland et al., 2007). Interestingly, CD200 knockout mice that had been infected with toxoplasma in a murine model of Toxoplasma encephalitis were able to clear the parasite more effectively due to the stronger inflammatory response that occurred (Deckert et al., 2006). A recent study employing mRNA expression analysis of laser-dissected active and inactive multiple sclerosis lesions demonstrated downregulated expression of CD200 in both types of lesions, while CD200R expression was unaffected (Koning et al., 2007).
In this report, we compared the expression of CD200 and CD200R in brain tissues affected by AD and demonstrated a deficit of both. The expression patterns of CD200 were examined in human AD and ND brains in relation to AD pathology. We also demonstrated that CD200R expression by human microglia is significantly lower than by human macrophages, but that its expression in both cell types can be increased by the anti-inflammatory cytokines IL-4 and IL-13. Expression of both anti-inflammatory cytokines is generally lacking in human elderly brains.
Section snippets
Human brain tissues
Human brain tissue samples from non-demented (ND) and AD cases that had been diagnosed by a neuropathologist were obtained from the Sun Health Research Institute Brain Bank. Brain tissues were donated to the Sun Health Research Institute Brain and Body donation program with informed consent and the approval of the Sun Health Corporation Institutional Review Board (IRB). A total of 59 cases were used in this study; 28 of these cases were diagnosed as ND (10 female: 18 male with mean age 86.0 y).
Immunolocalization of CD200 in human elderly brain
The aim of this study was to characterize CD200 and CD200 receptor expression in elderly human brains, and to demonstrate whether there was a deficit in AD of one or both. Studies on CD200 expression in human brain have not previously been reported except to demonstrate neuronal expression in cerebellum, a brain region not affected by AD (Wright et al., 2001). Most of our studies at the protein level on human brain tissues (immunohistochemistry and immunoblot) were carried out using a custom
Discussion
In this report, we have focused on CD200 and CD200R expression in elderly human AD and ND brains, and also studied expression of CD200R in vitro in human neural-derived and macrophage cells. There have been many publications on potential roles for microglia and inflammation in AD pathogenesis (recent reviews Craft et al., 2005, Pereira et al., 2005), but studies of cellular anti-inflammatory systems in the brain are more limited. These systems include CD200/CD200R, CD47/CD172a and CD22/CD45 (
Acknowledgments
This work was supported by grants from the Alzheimer's Association and Michael J Fox Foundation for Parkinson's Research (DGW). The authors are indebted to Dr. Thomas G. Beach and Ms. Lucia Sue for providing tissue for these studies from the Sun Health Research Institute Tissue Bank. The Brain Donation Program is supported by the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s
References (66)
- et al.
CD200 and membrane protein interactions in the control of myeloid cells
Trends Immunol.
(2002) - et al.
SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling
J. Biol. Chem.
(2005) - et al.
Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs
Mod. Path.
(2005) - et al.
Elevated neuronal expression of CD200 protects Wlds mice from inflammation-mediated neurodegeneration
Am. J. Pathol.
(2007) - et al.
Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis
Am. J. Pathol.
(2007) - et al.
“Eat me” and “don't eat me” signals govern the innate immune response and tissue repair in the CNS: emphasis on the critical role of the complement system
Mol. Immunol.
(2003) - et al.
mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Neurobiol. Aging
(2006) - et al.
Identification of cathepsin B as a mediator of neuronal death induced by A{beta}-activated microglial cells using a functional genomics approach
J. Biol. Chem.
(2004) - et al.
The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer's disease
J. Biol. Chem.
(1998) - et al.
CD200 immunoadhesin suppresses collagen-induced arthritis in mice
Clin. Immunol.
(2001)
Anti-CD200R ameliorates collagen-induced arthritis in mice
Clin. Immunol.
Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins
Int. Rev. Neurobiol.
Signaling mechanisms, interaction partners, and target genes of STAT6
Cytokine Growth Factor Rev.
Constitutively active STAT6 predisposes toward a lymphoproliferative disorder
Blood
Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism
Exp. Neurol.
Inflammatory processes in Alzheimer's disease
Prog. Neuro-psychopharmacol. Biol. Psychiatry
CD200 is a new prognostic factor in multiple myeloma
Blood
CD200: a putative therapeutic target in cancer
Biochem. Biophys. Res. Commun.
Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus
J. J. Biol. Chem.
Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and their association with clinical outcome, troponin T and C-reactive protein in patients with acute coronary syndromes
Clin. Biochem.
The inhibitory CD200R is differentially expressed on human and mouse T and B lymphocytes
Mol. Immunol.
Expression of CD200 on epithelial cells of the murine hair follicle: a role in tissue-specific immune tolerance?
J. Invest. Dermatol.
Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms
Int. J. Dev. Neurosci.
Characterization of human cd200 glycoprotein receptor gene located on chromosome 3q12–13
Gene
CD200 receptor family members represent novel DAP12-associated activating receptors on basophils and mast cells
J Biol. Chem.
Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function
Immunity
Blocking CD200–CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats
Ocul. Immunol. Inflamm.
Mice lacking CD200R1 show absence of suppression of lipopolysaccharide-induced tumor necrosis factor-alpha and mixed leukocyte culture responses by CD200
Transplantation
Discrete monoclonal antibodies define functionally important epitopes in the CD200 molecule responsible for immunosuppression function
Transplantation
Loss of surface CD200 on stored allogeneic leukocytes may impair anti-abortive effect in vivo
Am. J. Reprod. Immunol.
Placental trophoblast from successful human pregnancies expresses the tolerance signaling molecule, CD200 (OX-2)
Am. J. Reprod. Immunol.
beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis
J. Neurosci.
Neuroinflammation: a potential therapeutic target
Expert Opin. Ther. Targets
Cited by (212)
Brain endothelial CD200 signaling protects brain against ischemic damage
2024, Brain Research BulletinAngiotensin-converting enzyme inhibitors and statins therapies-induced changes in omics profiles in humans and transgenic tau mice
2023, Biomedicine and PharmacotherapyMicroglia in epilepsy
2023, Neurobiology of DiseasePharmacological targeting of microglia dynamics in Alzheimer's disease: Preclinical and clinical evidence
2022, Pharmacological Research