Elsevier

Neuroscience

Volume 405, 1 May 2019, Pages 118-136
Neuroscience

Review
Role of the CD200-CD200R Axis During Homeostasis and Neuroinflammation

https://doi.org/10.1016/j.neuroscience.2018.10.030Get rights and content

Highlights

  • Microglial activation is regulated by neurons, through the CD200-CD200R axis.

  • Effects of CD200-CD200R are different under homeostatic or inflammatory situations.

  • CD200-CD200R1 modulation is done by inhibiting pro-inflammatory microglial activation.

  • CD200-CD200R is a promising candidate to tackle chronic neuroinflammatory diseases.

Abstract

Microglia are considered to be the resident macrophages of the CNS and main effector of immune brain function. Due to their essential role in the regulation of neuroinflammatory response, microglia constitute an important target for neurological diseases, such as multiple sclerosis, Alzheimer’s or Parkinson’s disease. The communication between neurons and microglia contributes to a proper maintenance of homeostasis in the CNS. Research developed in the last decade has demonstrated that this interaction is mediated by “Off-signals” – molecules exerting immune inhibition – and “On signals” – molecules triggering immune activation. Among “Off signals”, molecular pair CD200 and its CD200R receptor, expressed mainly in the membrane of neurons and microglia, respectively, have centered our attention due to its unexplored and powerful immunoregulatory functions. In this review, we will offer an updated global view of the CD200-CD200R role in the microglia-neuron crosstalk during homeostasis and neuroinflammation. Specifically, the effects of CD200-CD200R in the inhibition of pro-inflammatory microglial activation will be explained, and their involvement in other functions such as homeostasis preservation, tissue repair, and brain aging, among others, will be pointed out. In addition, we will depict the effects of CD200-CD200R uncoupling in the etiopathogenesis of autoimmune and neurodegenerative diseases. Finally, we will explore how to translate the scientific evidence of CD200-CD200R interaction into possible clinical therapeutic strategies to tackle neuroinflammatory CNS diseases.

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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