Abstract
G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. They are considered as the most successful therapeutic targets for a broad spectrum of diseases. Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). It is the leading cause of non-traumatic disability in young adults. Great progress has been made over the past few decades in understanding the pathogenesis of MS. Numerous data from animal and clinical studies indicate that many GPCRs are critically involved in various aspects of MS pathogenesis, including antigen presentation, cytokine production, T-cell differentiation, T-cell proliferation, T-cell invasion, etc. In this review, we summarize the recent findings regarding the expression or functional changes of GPCRs in MS patients or animal models, and the influences of GPCRs on disease severity upon genetic or pharmacological manipulations. Hopefully some of these findings will lead to the development of novel therapies for MS in the near future.
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Introduction
Multiple sclerosis (MS), also known as disseminated sclerosis or encephalomyelitis disseminata, is an inflammatory disease that is characterized by immune-mediated demyelination and neurodegeneration of the central nervous system (CNS). It leads to substantial disability through deficits of sensation and of motor, autonomic, and neurocognitive functions. The disease onset usually occurs in young adults between 20 to 40 years of age 1,2 with a prevalence that ranges between 2 and 150 per 100 000 3. The disease is usually not life-threatening, but its socioeconomic importance is second only to trauma in young adults 4,5.
CD4+ T-cell-mediated autoimmunity has long been accepted as one of the most important aspects of MS pathogenesis, especially for the early initiation of the disease 6,7. T-helper type 1 (Th1) cells, characterized by the production of interferon-γ (IFN-γ), have been considered the type of effector T-helper cells that mediate the pathogenesis of MS. Subsequent studies have revealed that the IL-17-expressing T-helper cells (Th17) are also involved and are at least as critical as Th1 cells in this disease. Mice with fewer Th17 cells are less susceptible to experimental autoimmune encephalomyelitis (EAE) 8,9, a mouse model of MS; and IL-17-expressing T cells have been found in lesions of brain tissues from patients with MS 10.
There are several types of MS, including Benign MS, Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS), and Malignant MS (also known as Marberg Variant MS). RRMS is the most frequent (85%-90%) form and affects women about twice as often as men. Patients tend to experience an attack or series of attacks (exacerbations) followed by complete or partial remission. Most RRMS patients later develop SPMS. At that stage, there are no real periods of remission, but only breaks in attack duration with no real recovery from symptoms. About 10%-15% of patients presenting with insidious disease onset and steady progression are termed PPMS 7. It is characterized by gradual clinical decline with no real or distinct periods of remission. Magnetic resonance imaging (MRI) 11 or histopathological evaluation 12,13 also revealed heterogeneity in morphological alterations of the brain in different patients. It is still not clear which factors may contribute to the different disease courses and the heterogeneity in clinical presentations. Complex genetic effects and environmental components that translate into different immune abnormalities and/or increased vulnerability of CNS tissue to inflammatory insults or reduced ability to repair damage are certainly involved. Relatives of people who have the disease have an increased risk; if a patient with MS has an identical twin, that twin's risk climbs to more than 25% 4,14. But when a team of US researchers compared the complete genomes of twin females with each other, they failed to find any genetic differences that might cause MS 15. This observation indicates that the environmental stress might also play an important role in eventually triggering the pathogenesis of MS.
G protein-coupled receptors (GPCRs), also known as 7-transmembrane receptors, are the largest family of cell surface receptors involved in transmitting extracellular environmental signals into the cells. These receptors are activated by a wide variety of stimulations, including light, odorant molecules, peptide and non-peptide neurotransmitters, hormones, growth factors, lipids, etc. 16. The GPCR family comprises approximately 2% of the human genome and remains a central focus in basic pharmacology studies and drug discovery efforts 17. After agonist binding, the activated receptors catalyze the exchange of GDP for GTP on the α-subunit of heterotrimeric G proteins (composed of α-, β-, and γ-subunits), which in turn engages conformational changes that lead to the dissociation of the Gα from the dimeric Gβγ subunits 18. Both the Gα- and Gβγ- subunits can convey the extracellular signals by activating or suppressing downstream effector molecules, such as adenylyl and guanylyl cyclases, phosphodiesterases, phospholipases, phosphoinositide 3-kinases (PI3K), ion channels and other signaling components 16.
GPCRs have emerged as the most important targets for human therapeutics due to their large numbers and critical roles in the physiology of vital systems, such as cardiovascular, nervous, immune, metabolic, and endocrine systems. The prominent roles of GPCRs in cancer are also well recognized 19,20. These receptors are the target of > 50% of the current therapeutic agents on the market, including more than a quarter of the 100 top-selling drugs with benefits in the range of several billion US dollars each year. Here, we review recent progress on the roles of GPCRs in the pathogenesis of MS and hope that some of these receptors might become new therapeutic targets for this disease in the near future.
GPCRs involved in MS or EAE
Adenosine receptors
Dysfunction of adenosinergic system has been implicated in the development of MS in humans and EAE in animals. Blood adenosine level decreases greatly in MS patients 21. Among the four known subtypes of adenosine receptors – referred to as A1, A2A, A2B, and A3, the role of A1 in MS pathology has been intensively studied in both clinical samples and animal models. A1 was selectively diminished on cells of monocyte/macrophage lineage in both brain and blood samples from MS patients. This reduction potentially led to increased macrophage activation and CNS inflammation 21,22. In animal model, the A1 knockout mice developed a severe progressive-relapsing form of EAE with extensive inflammation and demyelination in CNS compared with the corresponding controls 23. Conversely, treatment with the A1 receptor agonist ADAC reduced spinal cord injuries in EAE mice 23. Caffeine, a non-selective antagonist of adenosine receptors, has also been shown to alleviate EAE in mice and rat 23,24,25. It has been postulated that chronic treatment with caffeine may benefit EAE animals by upregulating A1 receptor and TGF-β, and suppressing IFN-γ 25. These results suggest that adenosine might act through the A1 receptor to suppress inflammation and that dysfunction of A1 contributes to the pathogenesis of MS.
On the other hand, a recent study unexpectedly discovered that mice with a genetic deficiency in CD73, an extracellular nucleotidase critical for the generation of extracellular adenosine, are highly resistant to MOG-induced brain and spinal cord injury 24. Such reduction in EAE severity was not due to the lack of responsiveness of T cells, since CD4+ T cells from CD73−/− mice secreted more proinflammatory cytokines than wild-type mice and were able to induce EAE when transferred into naive CD73+/+ recipients. This correlates well with other reports that adenosine is an anti-inflammatory mediator. It seems that adenosine concentration in the CNS, possibly surrounding the choroid plexus epithelium, is critical for pathogenic T-cell infiltration, as the CD73−/− mice had fewer infiltrating lymphocytes in their CNS compared with wild-type mice even though their T cells were highly activated. In the same study, the authors also found that pharmacological blockade of the A2A receptor with SCH58261 attenuates EAE pathology 24. These results are quite controversial because A2A receptor is recognized as a major mediator of anti-inflammatory responses. Activation of A2A has been reported to suppress key components of the inflammatory process, including leukocyte recruitment, phagocytosis, pro-inflammatory cytokine production, and immune cell proliferation 26,27. These findings have already led to the clinical testing of A2A agonists in the treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and diabetic foot ulcer 27,28,29. The beneficial effect of A2A antagonist in EAE animals suggests that A2A receptors in the CNS might play an opposite role compared to the A2A receptors expressed on immune cells, though the functions of CNS A2A receptors are yet to be defined in autoimmune diseases. Using A2A knockout mice would certainly help to clarify the seemingly different roles of the periphery and CNS A2A receptors. It is quite surprising that no EAE studies have been conducted on the A2A knockout mice considering that these animals have been available for quite some time 30,31.
Unique among the four adenosine receptors, A2B is a low-affinity receptor for adenosine. Adenosine activates A1, A2A, and A3 receptors with EC50 values between 10 nM and 1 μM, whereas A2B receptor activation generally requires adenosine levels that exceed 10 μM 32. The physiological adenosine concentrations are lower than 1 μM, so activation of the A2B receptor is believed to require pathological conditions such as ischemia, trauma, inflammation or other types of stress 33. Though its functions in MS or EAE are not clear, A2B has been reported to play pro-inflammatory roles in both rodent and human asthma and COPD. Activation of A2B has been demonstrated to increase the production of IL-6 and IL-19 from mast cells, bronchial smooth-muscle cells, bronchial epithelial cells, and lung fibroblasts 34. In fact, CVT-6883, an A2B-selective antagonist, is under clinical investigation for the treatment of COPD 27. A2B is also believed to be involved in inflammatory bowel diseases. A2B receptors are upregulated in gut tissue during both human and murine colitis 35, and A2B blockade 36 or knockout 37 suppresses intestinal inflammation and attenuates the course of disease in murine colitis.
Though it is still unclear whether the A3 receptor is involved in MS, this receptor has been implicated to mediate the inhibition of TNF-α production by adenosine 38,39. Anti TNF-α drugs are remarkably effective in several autoimmune diseases, including rheumatoid arthritis, Crohn's disease, psoriasis and ankylosing spondylitis 40. Blocking TNF-α with antibodies or soluble TNF receptors also decreased EAE severity in animals 41. Unfortunately, such treatments have been found to be harmful rather than beneficial in human MS trials 42,43. A3 has also been found to be overexpressed in inflammatory tissues 44 and the PBMCs of arthritic animals 45. These findings warrant further investigations of this receptor in the pathogenesis of EAE or MS.
While the precise roles of adenosine and adenosine receptor subtypes in the development of MS and EAE remains to be clarified, the above findings clearly highlight the critical involvement of adenosine and adenosine receptors in inflammation and autoimmunity.
Adrenergic receptors
Accumulating evidence over the past few decades has documented that the brain communicates with the periphery immune system via two major pathways. The first pathway involves activation of the hypothalamic-pituitary-adrenal axis and the eventual secretion of corticosteroids from the adrenal cortex (reviewed in 46). The second pathway involves activation of the sympathetic nervous system (SNS) and the release of the various neural transmitters (reviewed in 47). As one of the major neural transmitters from the SNS, the catecholamine norepinephrine elicits its biological functions by activation of α1-, α2-, and β-adrenergic receptors 47.
Results from a series of studies show that the expression of adrenergic receptors, especially β-adrenergic receptors, changes significantly in both MS patients and EAE animals, when compared with the related controls. An early study with the Lewis rat acute EAE model indicated that in response to immune challenge, the splenic noradrenaline content fell significantly, accompanied by an increase in lymphocyte β-receptor density. These changes were considered as early indicators of immune reactivity 48. Similarly, in the MRL-lpr/lpr mouse, a genetic model of the human autoimmune disease systemic lupus erythematosus, noradrenergic innervation and noradrenaline content were reduced in the spleen prior to the onset of observed splenomegaly and remained reduced at all ages examined 49. In MS patients, increased β-adrenergic receptor density on PBMCs, including lymphocytes, has been well documented 50,51,52,53,54,55. This increase in β-adrenoreceptor density has been shown to be correlated with the expression of high affinity IL-2 receptors (IL-2R) on PBMCs and disease activity of RRMS. In vitro studies showed that β-agonist stimulation of PBMCs reduces the IL-2R expression and suppresses cell proliferation following mitogenic stimulation 51. This observation may indicate a recovery role for the enhanced β-adrenoceptor expression in MS. β2-adrenergic receptor is expressed on Th1 but not on Th2 cells 56. Given that cellular Th1 immune activity is considered to be one of the major contributors to disease activity in MS, increased expression of β2-adrenoreceptor may reflect activation of Th1 cells and a predominant cellular immune activity. Adrenergic receptors have also been reported to modulate cytokine production in dendritic cells (DCs) and affect their Th cell-priming ability 57. In particular, activation of β2-adrenergic receptors in DCs hampered IL-12, but stimulated IL-10 production resulting in reduced migration and Th1 priming 58,59. In contrast, more recent studies indicated that activation of β2-adrenergic receptors in DCs might lead to a dominant Th2/Th17-promoting phenotype in response to immunogenic protein or pathogen stimulation 60.
Another interesting phenomenon is the lacking of the astrocytic β2-adrenergic receptor in MS patients. β2-adrenoceptor has been identified on all GFAP-positive astrocytes in white matter and the optic nerve of healthy human and normal animals 61,62, and astrocytes are the main cellular target of norepinephrine terminals in the brain 63. However, in MS patients, this receptor could neither be visualized on astrocytes in normal-appearing white matter nor in reactive astrocytes in chronic active and inactive plaques, although it was normally present on neurons 61,64. Astrocytes are considered the primary APCs of the CNS in EAE models. Mice astrocytes can express MHC class II and B-7 co-stimulatory molecules, which are necessary for the efficient activation of naive T cells 65, and have potential for processing and presenting CNS auto-antigens to pro-inflammatory T cells 66. In normal conditions, the expression of MHC class II molecules are tightly suppressed by norepinephrine via β2-adrenergic receptor activation 67,68. Norepinephrine also inhibits the astrocytic expression of proinflammatory cytokines through the IκBα/NFκB pathway 69,70. The loss of astrocytic β2-adrenergic receptor might explain the presence of MHC class II on astrocytes and the increased pro-inflammatory cytokine levels in MS lesions. What causes the loss of astrocytic β2-adrenergic receptor in MS patients remains unclear, though a 'hit and run' viral infection model has been proposed 71.
Compounds regulating the adrenergic receptors have been used to treat EAE and MS. Nonselective β-adrenergic agonist isoproterenol and the β2-specific agonist terbutaline significantly suppressed both the first acute attack and the number of relapses in EAE Lewis rats 72. Other β2-adrenergic agonists, such as salbutamol and albuterol, have been proposed to be used as add-on therapy in patients with MS 71,73,74,75. In a recent trial with albuterol as an add-on treatment to glatiramer acetate therapy, improvement in the MS functional composite and a delay in the time to the first relapse were observed in the glatiramer acetate plus albuterol group 76. Other modulators of adrenergic receptors have also been reported to benefit EAE animals or MS patients. Prazosin, an α1-adrenergic receptor antagonist, suppressed the clinical and histological expression of EAE in the Lewis rat 77,78,79. Tizanidine, an α2-adrenergic receptor agonist, is a very useful medication in patients suffering from spasticity caused by MS 80,81.
Cannabinoid receptors
The medicinal use of Cannabis sativa (marijuana) can be traced back for centuries. But the existence of an 'endocannabinoid system' has only gained appreciation in the past few decades. This system consists of endocannabinoids (arachidonoylethanolamine (AEA), 2-arachidonoyl glycerol, 2-arachidonyl glyceryl ether (noladin ether), N-arachidonoyl-dopamine, virodhamine, etc.), their synthesizing/degradation enzymes and their receptors. There are two major types of cannabinoid receptors, termed CB1 and CB2. But other receptors, such as vanilloid receptor, GPR55 and GPR119 have also been reported to be activated by cannabinoids 82,83,84. The CB1 receptor is mainly expressed in the CNS, but also in the lungs, liver and kidneys. The CB2 receptor is mainly expressed in the immune system and in hematopoietic cells. Recently, CB2 has also been described in microglia and neuronal progenitor cells, but with few exceptions, it is not expressed by neurons within the CNS 82,85.
Both CB1 and CB2 are Gαi-coupled GPCRs. Activation of these receptors leads to inhibition of adenylate cyclase activity, reduced cAMP level, decreased activity of PKA, and eventual reduction in cytokine production and synaptic transmission 86. Activation of these receptors showed protective effects in various EAE models. Using the Theiler's murine encephalomyelitis virus (TMEV) model, the synthetic cannabinoids WIN 55212-2, ACEA, and JWH-015 significantly improved the neurological deficits in a long-lasting way 87,88. In a rat EAE model, decreased endocannabinoid level was reported in the brain and activation of cannabinoid receptors reduced the neurological impairment 89. The non-selective cannabinoid receptor agonist WIN-2 was found to ameliorate the clinical signs and diminish the cell infiltration into the spinal cord in a passive EAE rat model 90
The CB1 receptor was the initial focus of attention for studies using cannabinoids to treat EAE, because the activation of CB1 was believed to inhibit synaptic transmissions, which might contribute to spasticity, tremor and paralysis in EAE 91,92,93. These studies provide objective evidence to support the claims of MS patients that cannabinoids may have a benefit in symptom management 94. The beneficial effects were further supported by recent clinical trials with medical cannabis extracts 95. More direct evidence for the protective roles of CB1 receptor came from a study in a conditional knockout EAE model in which the neuronal CB1 was selectively deleted. In such animals, the cannabinoid-mediated EAE suppression was abolished 96.
In the same study, Maresz et al. 96 also reported that CB2 receptor expressed by the pathogenic T cells was critical for controlling inflammation associated with EAE. CB2-deficient T cells in the CNS of EAE animals exhibited reduced levels of apoptosis, a higher rate of proliferation, and increased production of inflammatory cytokines, resulting in more severe clinical symptoms. Palazuelos et al. 97 also found that CB2 knockout mice showed exacerbated clinical score of EAE; and the underlying mechanism might involve the extensive recruitment of immature bone marrow-derived CD34+ myeloid progenitor cells towards the spinal cords in CB2 knockout EAE mice. The immunosuppressive effect of CB2 activation was also supported by studies with selective CB1/CB2 agonists/antagonists. Ni et al. 98 demonstrated that the therapeutic effect of WIN55212-2, a non-selective CB1/CB2 agonist, could be blocked by CB2 antagonist SR144528, but not by CB1 antagonist SR141716A. JWH-015, a cannabinoid with a relatively high selectivity for CB2, was reported to suppress microglial activation 99. O-1966, a selective CB2 agonist 100, was found to significantly improve the motor function in the chronic EAE model, the remitting-relapsing model and the adoptive transfer model 101. Administration of HU-308, with a selectivity of ∼500× for CB2 vs CB1 102, improved EAE symptoms and reduced spinal cord lesions and microglial activation 97. Unlike CB1, CB2 activation is not associated with psychoactive effects. Therefore, targeting CB2 with selective agonists might be a more attractive way to treat MS.
It is also interesting to notice that the key components of the endocannabinoid system are all altered in MS patients. AEA and palmitoylethanolamide (PEA) were found to be higher in RRMS samples compared to controls. AEA, PEA, and oleoylethanolamide were also increased in the plasma of SPMS patients; PPMS patients had higher AEA plasma levels compared to controls. mRNA level of fatty acid amide hydrolase, the enzyme responsible for the degradation of endocannabinoids, was decreased in SPMS but not in RRMS or PPMS blood. CB1 and CB2 mRNAs were increased in the PPMS patients 103,104. The fact that all these alterations will lead to the activation of the endocannabinoid system suggests that the body might employ these as a mechanism to compensate for the over-activation of immune responses.
Chemokine receptors
Chemokines are cytokines initially characterized to be associated with leukocyte chemotaxis and inflammatory responses. Chemokines are classified on the basis of their structural properties, regarding the number and position of the conserved cysteine residues at the amino-terminal, into two major (CXC and CC) and two minor (C and CX3C) subfamilies 105,106. Chemokines were the first members of cytokine family to be shown to interact with GPCRs. Chemokine receptors comprise 10 CCR family members, 7 CXCR family members and other receptors including XCR1, CCRL1 and 2, and CX3CR1. Three decoy receptors, D6, DARC, and CCX-CKR (Chemocentryx-chemokine receptor), which bind chemokines with high affinity but do not elicit signal transduction, have also been reported 107. Many chemokines bind multiple receptors and most receptors bind multiple chemokines, suggesting the possibility of functional redundancy, which is also likely to be modulated by both the spatial and temporal control of expression. Chemokine receptors signal through heterotrimeric G-proteins, which in turn regulate diverse signal transduction pathways, including intracellular calcium, mitogen-activated protein kinases, PLCβ, PI3K, Ras, and Rho GTPases pathways, etc. 108. These signal mechanisms are believed to be responsible for cell movement beyond immune cell trafficking, as they also regulate other processes, such as hematopoiesis 109, angiogenesis 110, and organogenesis, including CNS formation 111.
The infiltration of leukocytes into the CNS is an essential step in the neuro-pathogenesis of MS. Leukocyte extravasation from the bloodstream is a multi-step process that depends on fluid dynamics within the vasculature and molecular interactions between circulating leukocytes and the vascular endothelium. An important step in this cascade is the binding of chemokines displayed on the vascular endothelial cell surface to chemokine receptors on circulating leukocytes, initiating intracellular signaling that leads to integrin activation, leukocyte arrest, and extravasation 112. Indeed, during the pathogenesis of MS or EAE, the expression of many chemokines and/or their receptors has been found to be altered significantly in the demyelinating plaques or the periphery immune tissues (summarized in Table 1).
Modulating immune cell migration into the CNS may represent an ideal way of combating neuro-inflammation, and accurately determining which processes or physiological roles may be regulated by a given chemokine or its receptors is crucial. The best means of investigating the actual functions of chemokines and their receptors are probably those using gene-manipulated (transgenic or knockout) mice and specific pharmacological blockers of the receptors (summarized in Table 2). Even though the attempt to translate knowledge from the animal models to the human situation is criticized, these models have rapidly led to an understanding of chemokine signaling pathways and have provided the basis for their use as therapeutic targets.
The recent failures of CCR1 antagonists BX471 (Berlex/Schering), MLN 3701 and MLN 3897 (Millennium) and CCR2 antagonist MK-0812 (Merck), which showed promising results in animal models 113, in treating MS in phase II clinical trials highlighted the difficulty of this animal-to-human translation 114. Functional redundancy of chemokines and their receptors might contribute to this problem. Moreover, the redundancy could vary between species, making it difficult to predict what the outcome of an antagonist tested in animal models will be in humans. Finally, the heterogeneity of MS 114,115 might further complicate the problem. Despite these difficulties, pharmaceutical companies still consider chemokine receptors as promising therapeutic targets. Almost every major company has a list of potential blockers in clinical development for different indications, including MS (summarized in Table 3).
Leukotriene receptors
Leukotrienes are potent pro-inflammatory mediators derived from arachidonic acid via the sequential actions of cytosolic phospholipase A2α (cPLA2α), 5-lipoxygenase (5-LO), and LTA4 hydrolase (LTA4H) for LTB4, or LTC4 synthase (LTC4S) for cysteinyl leukotrienes (CysLTs, including LTC4, LTD4, and LTE4) 116. There have been contradictory reports regarding the change of leukotriene levels in MS patients and animal models. Some studies found that the LTB4 and LTC4 levels are significantly increased in the cerebrospinal fluid (CSF) of MS patients compared with the controls 117,118. But no significant difference exists in LTC4 production between MS and control peripheral blood monocytes and macrophages 118,119. These results were also verified in the animal model of EAE 120. Other studies, however, found normal CSF concentrations of leukotrienes 121. Such discrepancies have been attributed to the difficulties in measuring leukotrienes accurately in body fluids.
However, the studies of the key enzymes of the leukotriene biosynthesis pathways revealed important roles of leukotrienes in the pathogenesis of MS. The biosynthesis of leukotrienes in inflammatory cells begins with the cleavage of arachidonic acid from nuclear membrane glycerophospholipids by cPLA2α. Marusic et al. 122,123 reported that cPLA2α-deficient mice are resistant to EAE and blocking cPLA2α with specific inhibitors prevents EAE development and greatly reduces antigen-induced production of Th1-type cytokines and IL-17. Another key enzyme, 5-LO, which catalyses the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid and subsequently the unstable precursor LTA4, was found to be upregulated in both MS lesions and EAE brains by microarray analysis 124. 5-LO-specific inhibitors-treated guinea pigs showed significantly lower histological inflammation and better clinical outcome compared with controls upon EAE induction 120,125,126.
The biological effects of LTB4 are mediated via two GPCRs, BLT1 and BLT2 127. CysLTs also activate two GPCRs, namely CysLT1 and CysLT2 128. Inhibition of LTB4 receptors by antagonists or gene knockout alleviates disease pathology in EAE. An early study found that LTB4 receptor antagonist treatment significantly reduced, but did not completely inhibit the cachectic response in a guinea pig EAE model 129. Similar results were also observed in a murine model of EAE upon antagonist treatment 130. A recent study with BLT1-knockout mice found that BLT1 deficiency led to delayed onset and less severe symptoms of EAE, and BLT1−/− lymphocytes showed impaired proliferation ability and decreased cytokine production 127. Our recent study with two anti-asthmatic drugs (montelukast and zafirlukast) targeting CysLT1 indicated that blocking CysLT1 could alleviate CNS inflammatory cell infiltration and pathogenesis of EAE by reducing the permeability of the blood brain barrier (BBB) and the chemotaxis of pathogenic T cells 131.
Opioid receptors
Opioid compounds such as morphine modulate nociceptive pathways in the nervous system and produce powerful analgesia, and are used to treat various types of pain. It has also been noticed for a long time that opioids can alter the immune responses. Acute or chronic administration of opioids is known to have inhibitory effects on humoral and cellular immune responses, including antibody production, natural killer-lymphocyte activity, cytokine expression, and phagocytic activity 132,133,134. Increased morbidity and mortality due to artificial infection and faster cancer progression have been well documented in animal studies with morphine treatment 134,135. However, from other studies it emerges that not all opioids induce the same immuno-suppressive effects 136,137.
The endogenous opioid system is comprised of native opioid peptides and four opioid receptors: delta, mu, kappa receptors, and opioid receptor-like 1 138. Preclinical investigations utilizing animal models, as well as clinical observations with MS patients, suggested alteration of endogenous opioid systems in the disease. In the TMEV model of MS, mRNA levels of the mu, delta, and kappa opioid receptors were significantly decreased in the spinal cord at days 90, 150, and 180 post infection 139. The loss of opioid receptors might partially explain the common central neuropathic pain in MS patients 140. Pregnant woman usually have higher levels of endogenous opioids 141. They experience remission of MS and have fewer relapses during their pregnancy. However, these women exhibit a marked increase in relapse rate 3 months after delivery, when endogenous opioid levels are decreased 142,143. These findings suggest that one or more of the elevated opioids are acting with relevant receptors to attenuate the pathogenesis of MS. However, Gironi et al. 144 have reported a reduction of β-endorphin levels in PBMCs from patients with clinically inactive MS, but demonstrated an increase of β-endorphin in PBMCs from patients experiencing a relapse. The same group also found that β-endorphin level varies in different forms of MS. The lowest PBMC β-endorphin level was observed in primary and secondary progressive forms of MS, while the highest level was found in patients with benign and relapsing remitting forms of MS 145. Treatment with IFN-β seems to induce an increase of this opioid in MS patients 144. The increase of β-endorphin concentration during a clinical relapse may represent a possible control mechanism aimed at downregulating the inflammatory process.
Opioids have been used to treat EAE or MS. Met-enkephalin, an endogenous opioid, inhibited the onset and progression of EAE 146. A preliminary clinical trial showed that intrathecally given met-enkephalin exerted a beneficial effect on 13 patients with chronic severe progressive MS 147. Rats treated with MR 2034, a kappa opioid receptor agonist, showed a pronounced suppression of EAE clinical signs, CNS histological lesions, and anti-myelin basic protein antibody production 148. However, other reports have shown that naltrexone (NTX), a non-selective opioid receptor antagonist, has protective effects on both EAE animals and MS patients. Zagon et al. 149 demonstrated that low-dose NTX (LDN, 0.1 mg/kg) markedly reduced the severity and disease index of the treated mice, and over 33% of the MOG-treated animals receiving LDN treatment did not exhibit behavioral signs of disease. On the other hand, high-dose NTX (HDN, 10 mg/kg) displayed no beneficial effect. A 6-month phase II multi-center pilot trial with LDN has been carried out in 40 patients with PPMS. A significant reduction of spasticity was observed at the end of the trial 150. The therapeutic effect of LDN might be explained by the elevated endogenous opioids and opioid receptors due to the temporary blockade of the opioid receptors 151,152,153.
These results suggest that endogenous opioids and their receptors may play important roles in the development of EAE and MS, though the exact ligand, receptor or their mechanisms remain to be elucidated. Nevertheless, LDN, which has been successful in the treatment of Crohn's disease 154, would represent a safe, non-toxic, and generically available agent for attenuating MS and possibly other autoimmune diseases.
Sphingosine-1-phosphate receptors
Sphingolipids were first identified in the ethanolic brain extracts in the 1870s and were named after the Greek mythological creature, Sphinx, because of their enigmatic nature 155. Sphingosine-1-phosphate (S1P) represents a minor constituent of total sphingolipids. It is found abundantly in vertebrate blood and lymph. With the discovery of five S1P receptors 156,157, designated S1P1-5, S1P is recognized as an important extracellular lipid mediator.
S1P receptors are ubiquitously but differentially expressed on all cells, including a wide range of cells that are involved in the development of MS. Genetic deletion of S1P1 in mice demonstrated that this receptor plays key roles in angiogenesis and vascular maturation 158, immune cell trafficking 159, endothelial barrier function 160, and vascular tone 110. Like S1P1, S1P2 and S1P3 are also widely expressed. S1P4 has a more restricted expression pattern and is detectable predominantly within immune compartments and leukocytes 161, and may play a role in regulating T-cell cytokine production 162. S1P5 is expressed primarily in the white matter of the CNS, but its precise role remains to be clarified.
MS is generally believed to be caused by the invasion of autoreactive T cells into the CNS, which leads to demyelination and axonal damage. The S1P1 receptor has been shown to regulate the recirculation of lymphocytes 163,164,165 and their egress from secondary lymphatic organs 159. Therefore, targeting S1P1 to reduce circulating T cells might be an effective treatment for MS and other autoimmune diseases.
Recently, fingolimod (FTY720), a non-selective S1P receptor modulator, has been approved by the US FDA as the first oral, first-line treatment for RRMS. It outperformed the established first-line therapy IFN-β1a in a 1-year, double-blind, and double-dummy phase III study (known as TRANSFORMS) 166. In animal studies, prophylactic administration of fingolimod completely prevented development of EAE features, whereas therapeutic administration significantly reduced the clinical severity of EAE 167,168. As a structural analog of sphingosine 169, fingolimod is phosphorylated in vivo by sphingosine kinase 2 170 to produce fingolimod-phosphate, which binds to four of the five S1P receptors (S1P1 and S1P3-5) with high affinity. Fingolimod-phosphate initially activates lymphocyte S1P1 but subsequently induces S1P1 internalization and downregulation, which prevents lymphocyte egress from lymphoid tissues, therefore reducing pathogenic lymphocyte infiltration into the CNS 163,171. Fingolimod is also reported to ameliorate EAE by suppressing both cellular and humoral immune responses 172.
Fingolimod is able to cross the BBB 173, and may therefore have direct CNS effects, which is unique compared to other immunologically targeted MS therapies. S1P receptors are also expressed in many CNS cells and have been shown to influence cell proliferation, morphology, and migration 174,175. S1P and S1P1 have been implicated to mediate the migration of neural stem cells towards sites of injury in the spinal cord 175. Recent studies in EAE also suggested a key role of the neuronal S1P1 in disease progression 176. Re-myelination has been documented in human MS lesions and animal models 177,178. S1P1 and S1P5 are both expressed on oligodendrocytes and may be involved in the re-myelination process. Fingolimod can increase the number of both progenitor and mature oligodendrocytes in vitro. It can protect oligodendrocytes from cell death induced by cytokines or the withdrawal of growth factors, and modulate process outgrowth 179,180. High levels of S1P1 and S1P3 are also found in astrocytes 181, a glial cell type that might act like immune cells to enhance the immune responses and inhibit myelin repair. S1P induces activation and proliferation of astrocytes in vitro, while injection of S1P into the striata of mouse brains induced astrogliosis 182. In a recent study with conditional knockout mice, EAE was attenuated and fingolimod efficacy was lost in mutants lacking S1P1 on GFAP-expressing astrocytes but not on neurons 183. Receptor rescue and pharmacological experiments supported the loss of S1P1 on astrocytes via functional antagonism by fingolimod-phosphate as a primary mechanism of fingolimod. S1P1 is also expressed and plays important physiological roles in neurons. Genetic deletion of S1P1 resulted in defective neuronal development 184. Fingolimod has been shown to display neuroprotective effect in both in vitro and EAE animal models 185.
Fingolimod thus represents a new generation of medicines for MS treatment with the advantages of oral administration, and beneficially affecting not only the immune system to reduce inflammatory damage but also the CNS to promote neuroprotection and repair. Fingolimod is a non-selective sphingosine receptor modulator. Targeting other receptors, especially the S1P3 receptor, has been reported to induce certain cardiovascular side effects 186. Pharmaceutical companies are currently developing more specific S1P1 agonists to avoid such potential problems. For example, ACT-128800, an orally available S1P1 receptor agonist ∼650-fold more selective for human S1P1 over S1P3 than the natural ligand, is currently under phase II clinical investigation to treat RRMS 187,188,189.
Other GPCRs
Many other GPCRs have also been reported to be involved in the pathogenesis of EAE. For example, blocking dopamine D2-like-receptors (including D2, D3, and D4) with antagonist L750667 promoted DC-mediated Th17 differentiation 190. This is consistent with a previous report that D2 receptor agonist bromocriptine displayed therapeutic effect on acute and relapsing EAE models 191. In contrast, SCH23390, a D1-like-receptor antagonist, inhibited DC-mediated Th17 differentiation and prevented EAE in mice 190.
Histamine also plays a key regulatory role in EAE and exerts its effect through four GPCRs designated H1, H2, H3, and H4 receptors. Histidine decarboxylase is the necessary enzyme to make histamine. The histidine decarboxylase-deficient mice are genetically unable to make histamine. EAE was found to be significantly more severe in these animals 192. H3R knockout mice also developed a more severe EAE and neuro-inflammation compared with the wild-type animals 193, indicating that the immunosuppressive effect of histamine might be mediated via H3R. However, H1R-deficient mice have been found to be more resistant to EAE induction than wild-type controls 194. Treatment with pyrilamine or hydroxyzine, the H1R antagonists, led to reduced clinical signs of EAE and brain mast cell activation 195,196,197. Results from a pilot open-label clinical trial also indicated that hydroxyzine can partially inhibit brain mast cell activation and reduce MS symptoms 198.
Increasing evidence suggests that the platelet-activating factor (PAF) and its receptor (PAFR) are involved in EAE and MS pathogenesis. PAF was upregulated in peripheral-blood leukocytes during EAE induction, and the receptor antagonist treatment or gene knockout led to alleviation of clinical signs 195,196,199,200. Polymorphism of PAFR gene has also been identified to be correlated with the susceptibility to MS in human 201.
Apart from leukotrienes, prostaglandins form another family of important signaling molecules derived from arachidonic acid. Prostaglandin E2 (PGE2) was found to be increased in the CSF of MS patients 118,202. Among the four PGE2 receptors, EP1-EP4, only the EP4-knockout significantly suppressed EAE induction. This was mimicked in wild-type mice and to a greater extent, in EP2-knockout mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization or preclinical phase 203,204. But ONO-AE3-208 administration at EAE onset had little effect on disease severity. In contrast, administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the BBB 204. Thus, PGE2 exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the BBB integrity through EP4 203,204.
Other GPCRs that have been reported to be involved in EAE or MS pathogenesis, such as serotonin receptors, GPR30, and a list of peptide receptors, are summarized in Table 4.
Conclusion
As summarized herein, a large body of evidence from both in vivo and in vitro studies suggests that GPCRs mediate important physiological or pathological functions in the development of MS (Figure 1). Targeted blockade or activation of GPCR-mediated signaling may provide novel approaches to treating MS. Given the current lack of effective pharmacological targets for the treatment of MS, the continued identification and study of GPCRs in MS pathogenesis may eventually lead to major breakthroughs and new pharmacological strategies. One of the best examples of targeting GPCRs to treat MS is the case of fingolimod (FTY720), an S1P1 receptor modulator. Application of this drug significantly reduced the relapse rates, the risk of disability progression, and MRI measures of disease activity in MS patients, as compared with IFN-β1a or placebo. More interestingly, as a wide variety of drugs or compounds targeting GPCRs have already been developed for the treatment of other human diseases, repositioning of these agents might greatly facilitate the development of novel therapies for MS or other autoimmune diseases. We anticipate an exciting future for the discovery of new drugs for MS by targeting GPCRs.
Pathogenesis of multiple sclerosis and critical roles of GPCRs. Studies with genetic manipulations and/or pharmacological interventions suggest that GPCRs mediate important processes in the development of EAE or MS: (I) T-cell activation; (II) T-cell egress from lymphoid tissues; (III) migration and infiltration of inflammatory cells from the periphery to the CNS; (IV) BBB integrity maintenance; (V) astrocyte activation; (VI) microglia activation; (VII) demyelination and neurotoxicity.
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Acknowledgements
We thank Dr Ru Zhang, Mr Wei Wei and Ms Jie Lv for discussion and critical reading of the manuscript. This work was supported by grants from the National Natural Science Foundation of China (31000399, 31171348, 90713047, and 31071227), and the Ministry of Science and Technology of China (2012CB910404, 2008DFB30150 and 2009ZX09302-001).
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Du, C., Xie, X. G protein-coupled receptors as therapeutic targets for multiple sclerosis. Cell Res 22, 1108–1128 (2012). https://doi.org/10.1038/cr.2012.87
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DOI: https://doi.org/10.1038/cr.2012.87
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