ReviewRole of the CD200-CD200R Axis During Homeostasis and Neuroinflammation
Section snippets
Dialogs in the brain: communication of microglial and other neural cells in both physiological and pathological situations
Microglial cells, considered to be the resident macrophages of the CNS, are derived from precursors coming from the yolk sac that invade the brain parenchyma during embryonic stages and subsequently proliferate, migrate and differentiate into ramified microglia (Ginhoux et al., 2013). In the healthy adult brain, microglia act as sentinels, continuously surveying the local micro-environment and interacting with the surrounding cells (Davalos et al., 2005, Nimmerjahn et al., 2005). Any
The CD200-CD200R axis
CD200, also formerly known as OX-2, is a protein present at the first line of immune defense that belongs to the immunoglobulin superfamily of cell-surface proteins (Barclay and Ward, 1982, Barclay et al., 1986, Wright et al., 2001). Human CD200 weighs 32 kDa, contains six glycosylation sites and has three possible CD200 membrane isoforms (UniProtKB – P41217), as well as soluble CD200 forms (Kos et al., 2014). Mouse CD200, as in humans, is a 32-kDa protein without isoforms. Because CD200 exerts
The immunomodulatory role of CD200-CD200R in microglia and CNS tissue protection
Before the identification of the specific inhibitory receptors regulating microglia, important immune inhibitory effects were demonstrated in vitro derived from the neuron-microglia communication (Lyons et al., 2007). This inhibitory effect was later determined to be partially mediated by CD200-CD200R1 binding (Lyons et al., 2007, Lyons et al., 2009, Lynch, 2014). Additional in vivo evidence demonstrated that, in homeostatic conditions, CD200-deficient mice showed microglia clusters formation,
Changes of CD200-CD200R during development and aging
Increasing evidence indicates that age is one of the factors regulating the expression and function of CD200-CD200R1. During aging, despite microglial CD200R expression being preserved, CD200 expression in neurons was progressively altered. Thus, with aging, several reports described the diminishing of CD200 expression in specific areas of the rodent brain, such as the hippocampus and the substantia nigra, which is accompanied by a greater pro-inflammatory micro-environment (Frank et al., 2006,
CD200-CD200R in autoimmune diseases: how to avoid microglia activation
The immunoregulatory role of CD200-CD200R in microglia highlights a possible key function of this axis in autoimmunity. Actually, the main focus is the experimental autoimmune diseases (Table 2), and among them, multiple sclerosis (MS).
Animal models of MS, principally EAE (for review see Constantinescu et al., 2011, Kipp et al., 2017, Procaccini et al., 2015), show a regulation of CD200 and CD200R expression over time after disease induction. In both experimental models and in MS patients,
Correlation with chronic neuroinflammation
While it is clear that the CD200-CD200R signal plays an important role in autoimmune diseases, the involvement of this axis in neurodegenerative diseases is still not completely known. Most studies in this regard have focused on two neurodegenerative disorders, Parkinson’s disease (PD) and Alzheimer’s disease (AD), due to the fact that aging is their major risk factor (Walker and Lue, 2013). As already explained above (see Section ‘Changes of CD200-CD200R during development and aging’), aging
Discussion
In the last few years, a deeper understanding of the effects of the CD200-CD200R axis in the regulation of CNS homeostasis and neuroinflammation has been progressively achieved. The main role of this axis is linked to the regulation of microglial activation by neurons, as they are the principal cells expressing CD200R and CD200, respectively. However, the expression of CD200 has been reported in other brain cells, such as endothelial cells, astrocytes and oligodendrocytes, opening the
Acknowledgments
The authors would like to thank Mr. Chuck Simmons, a native English-speaking Instructor of English of the Autonomous University of Barcelona for the proofreading of this manuscript. This work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2014-55459 and BFU2017-87843R).
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