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CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation

CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation fphar-07-00264 August 18, 2016 Time: 16:13 # 1 MINI REVIEW published: 22 August 2016 doi: 10.3389/fphar.2016.00264 CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation 1,2 1,3 1,2 1 Juan Zhou , Ian Burkovskiy , Hyewon Yang , Joel Sardinha and 1,2,3 Christian Lehmann 1 2 Department of Anesthesia, Dalhousie University, Halifax, NS, Canada, Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada, Department of Pharmacology, Dalhousie University, Halifax, NS, Canada The endocannabinoid system (ECS) is involved in many physiological processes and has been suggested to play a critical role in the immune response and the central nervous system (CNS). Therefore, ECS modulation has potential therapeutic effects on immune dysfunctional disorders, such as sepsis and CNS injury-induced immunodeficiency syndrome (CIDS). In sepsis, excessive release of pro- and anti-inflammatory mediators results in multi-organ dysfunction, failure, and death. In CIDS, an acute CNS injury dysregulates a normally well-balanced interplay between CNS and the immune system, leading to increased patients’ susceptibility to infections. In this review, we will discuss Edited by: potential therapeutic modulation of the immune response in sepsis and CNS injury by Rukiyah Van Dross-Anderson, manipulation of the ECS representing a novel target for immunotherapy. The Brody School of Medicine at East Carolina University, USA Keywords: endocannabinoid system, immune dysfunction, sepsis, central nervous system injury, Reviewed by: immunosuppression, GPR55, CNS injury-induced immunodeficiency syndrome Rafael Franco, University of Barcelona, Spain Nicholas V. DiPatrizio, INTRODUCTION University of California, Riverside, USA *Correspondence: The endocannabinoid system (ECS) is involved in many physiological processes including Juan Zhou metabolism, inflammation, pain, and neurotransmission (De Petrocellis and Di Marzo, 2009; [email protected] Pandey et al., 2009). It consists of endogenous cannabinoids (EC), cannabinoid receptors (CBR), and EC metabolizing enzymes (De Petrocellis and Di Marzo, 2009; Pertwee et al., 2010). Two Specialty section: major CBRs are identified: CBR type 1 (CB R) and CBR type 2 (CB R; Howlett et al., 2002). CB R 1 2 1 This article was submitted to are mainly expressed in the central nervous system (CNS) and a variety of non-neural peripheral Experimental Pharmacology and Drug tissues, including the vasculature and gut (Pertwee and Ross, 2002). CB R are primarily expressed Discovery, 2 a section of the journal on immune cells but are also identified in selected CNS areas and some peripheral tissues (Klein, Frontiers in Pharmacology 2005). Recently another G protein-coupled receptor, GPR55, has garnered much attention due to its activation by EC and its impact on the immune system (Pertwee, 2007; Yang et al., 2016a). Received: 06 May 2016 Accepted: 05 August 2016 Increasing evidence shows that enhanced EC levels occur during systemic inflammation, such Published: 22 August 2016 as in sepsis or following a CNS injury. Manipulation of the ECS may have therapeutic effects in inflammatory disorders. In this review, we will focus on modulation of CB and GPR55 receptors Citation: 2 Zhou J, Burkovskiy I, Yang H, on immune response in two inflammatory disorders, sepsis, and CNS injury. Both sepsis and CNS Sardinha J and Lehmann C (2016) injury cause the immune system to go through rather rapid and dramatic changes from pro- to anti- CB2 and GPR55 Receptors as inflammatory phases, which may end up costing patients their life. We suggest that the common Therapeutic Targets for Systemic mechanism for modulating and ultimately controlling the response of the immune system can be Immune Dysregulation. achieved through delicate interplay between the endocannabinoid, central nervous and immune Front. Pharmacol. 7:264. systems. doi: 10.3389/fphar.2016.00264 Frontiers in Pharmacology | www.frontiersin.org 1 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 2 Zhou et al. Immunomodulation by CB R and GPR55R et al., 1995; Carrier et al., 2004), while other studies have ECS IN SEPSIS shown inhibitory effects on leukocyte proliferation through the Sepsis is defined as a life-threatening organ dysfunction caused by activation of the CB R (Maresz et al., 2007; Basu and Dittel, 2011). a dysregulated host response to an infection (Singer et al., 2016). This inhibition maybe mediated by CB R-dependent promotion An initial infection with the ensuing systemic inflammatory of apoptosis in dendritic cells, splenocytes, and thymocytes, response becomes amplified, resulting in excessive release of with some diminished activity when CB R antagonists are used both pro- and anti-inflammatory mediators, causing multi-organ (Basu and Dittel, 2011). Additional evidence also supports the dysfunction, failure, and death (Kleinpell et al., 2006; Singer et al., role of CB R in the promotion of apoptosis. For example, 2016). Recently, the ECS has emerged as a potential therapeutic administration of the CB R agonist, JWH-015, induced apoptosis target in sepsis treatment due to its immune modulatory in thymocytes and diminished the proliferative potential of T functions. The effect of modulation of CB R, CB R, and GPR55 cells and B cells (Lombard et al., 2007). Administration of the 1 2 in sepsis-induced systemic inflammation will be described below. CB R antagonist, AM630, showed a reversal of the induction of T cell apoptosis by JWH-133 (another CB R agonist), strongly CB R implicating a CB R dependent mechanism (Singh et al., 2012). 1 2 Cannabinoid receptors type 1 are mainly pre-synaptic receptors This evidence suggests that activation of CB R may promote in axon terminals and their activation causes post-synaptic immune resolution by inducing apoptosis of immune cells, inhibition by preventing neurotransmitter release (Chevaleyre therefore minimizing excessive damage of the pro-inflammatory et al., 2006; Ladak et al., 2011). Manipulating the activity of cascade that occurs early on in sepsis. CB R at critical periods may play a therapeutic role in sepsis. Using an experimental sepsis model, we demonstrated that Studies have suggested that pre-synaptic CB R activation on activation of CB R by the selective CB R agonist, HU308, 1 2 2 autonomic nerves and vascular walls exacerbates the hypotension significantly reduced leukocyte adhesion in the microvasculature associated with septic shock through neurogenic mechanisms (Lehmann et al., 2012). Administration of EC degradation (Godlewski et al., 2004). However, studies using CB R knockout enzyme inhibitors, such as URB597 and JZL184, also decreased mice subjected to endotoxemia showed acute hypotension leukocyte activation in endotoxemic animals (Sardinha et al., indicating that other mechanisms are also responsible for 2014). However, reduced leukocyte activation by JZL184 is hypotension during systemic inflammatory conditions (Bátkai still present in endotoxemic CB R knockout mice, suggesting et al., 2004). In a lipopolysaccharide (LPS) induced experimental that other mechanisms are also involved in the ECS-mediated sepsis model, we demonstrated that inhibition of CB R by its immune regulation in sepsis. antagonist, AM281, significantly reduced leukocyte activation Cytokine production by immune cells plays a critical role and improved intestinal microcirculation (Kianian et al., 2014) in the inflammatory response and can be modulated through and iris microcirculation (Kelly et al., 2010; Al-Banna et al., CB R. Multiple pro-inflammatory cytokines, such as TNF-a, 2013). However, the exact mechanisms of CB R action in sepsis interleukin (IL)-1b, and IL-6, are released in the early stages of and septic shock are not yet completely understood and further the septic cascade. However, activation of the CB R by its agonist studies are still required. HU308 reduced plasma levels of pro-inflammatory cytokines in endotoxemic rats (Lehmann et al., 2012). Administration of the CB R EC, anandamide, decreased the levels of the proinflammatory Cannabinoid receptors type 2 are primarily expressed on immune cytokines IL-12 and IL-23 in vitro in activated microglial cells cells and represent an ideal target for immune modulation (Correa et al., 2009). In addition, T cell activation and release of (Klein, 2005). CB R are G -protein coupled receptors and signal IL-2 were inhibited by administration of the CB R agonist, JWH- 2 i 2 primarily through regulating cAMP levels depending on the 015, and this effect was eliminated by administration of the CB R duration of activation of the receptor (Rinaldi-Carmona et al., antagonist, AM630 (Börner et al., 2009). It was also demonstrated 1998; Börner et al., 2009; Basu and Dittel, 2011). CB R also that activation of CB R by HU308 enhanced the release of 2 2 signal through the mitogen-activated protein kinase (MAPK) IL-10, a prominent anti-inflammatory cytokine, suggesting an pathway by regulating the three major kinases: the extracellular immunosuppressive effect of CB R (Klein, 2005). signal-regulated protein kinases (ERK), p. 38, and c-Jun NH2- terminal kinases (Basu and Dittel, 2011). Both of these major GPR55 signaling pathways play important roles in CB R-mediated GPR55 was initially described as a novel cannabinoid receptor or immune modulating functions including effects on leukocyte putative “CB ” receptor due to its high affinity to cannabinoid activation, migration, proliferation, apoptosis, and cytokine ligands such as 19-THC, 2-AG, anandamide, and rimonabant, production (Basu and Dittel, 2011). In general, CB R activation independent of the presence of CB R and CB R (Sawzdargo 2 1 2 has shown an immune suppressive action, which can be exploited et al., 1999; Begg et al., 2005; Pertwee, 2007; Ryberg et al., for therapeutic benefit in inflammatory diseases such as sepsis. 2007). However, the limited sequence similarity between GPR55 A variety of in vitro studies have shown contradictory results and CBR does not support this concept (Baker et al., 2006). in terms of modulation of the immune response, mainly due Unlike the classical CB R and CB R signaling pathway, GPR55 1 2 to the use of non-selective cannabinoids (Miller and Stella, is coupled to Ga12 and Ga13 proteins, signaling through ras 2008). Some studies have shown that cannabinoids enhanced homolog gene family member A, Rho-associated protein kinase leukocyte proliferation in a dose dependent manner (Derocq and phospholipase C pathway activation. Increased intracellular Frontiers in Pharmacology | www.frontiersin.org 2 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 3 Zhou et al. Immunomodulation by CB R and GPR55R 2C required to develop a specific pharmacological target for precise Ca is followed to activate rhoA, Rac, and cdc42, thereby and designated immune modulation. phosphorylating ERK, resulting in modulation of leukocyte chemotaxis, proliferation, and cytokine production (Ryberg et al., ECS in CNS Injury 2007; Henstridge et al., 2009). Central nervous system injury includes traumatic brain injury, GPR55 is widely expressed in the CNS, immune system, and stroke, cerebral aneurysms, and spinal cord injuries. Survivors peripheral tissues and is involved in many physiological and from acute CNS injury often have complications due to pathophysiological processes (Ryberg et al., 2007; Henstridge infections. The incidence of fatal infections is linked to severity et al., 2011). In the immune system, GPR55 is highly expressed of CNS injury and the status of immune system (Klehmet in the spleen and leukocytes, and its role in the modulation et al., 2009; Shim and Wong, 2016). Following acute CNS of innate and adaptive immune responses suggests a potential injury, cell death occurs at the primary site and cytotoxins are therapeutic effect for sepsis (Staton et al., 2008; Lin et al., released, which trigger significant secondary cell death outside 2011; Schicho and Storr, 2012; Stanci ˇ c ´ et al., 2015). GPR55 acts the original injury area. In addition, function of the blood brain as an essential regulator in innate immunity via stimulatory barrier is impaired, allowing systemic inflammatory mediators effects in neutrophils, mast cells, monocytes, and natural and cells to enter the normally protected CNS tissue, leading killer (NK) cells (Balenga et al., 2011; Cantarella et al., 2011; to the pathology of a CNS injury, i.e., neuroinflammation. Schicho et al., 2011; Chiurchiù et al., 2015). GPR55 on NK The level of neuroinflammation is highly dependent on the cells and monocytes increase pro-inflammatory cytokines, cell severity, duration, and the anatomical context of the CNS cytotoxicity, and decrease monocyte-mediated endocytosis upon injury. To prevent the excessive action of pro-inflammatory activation by LPS (Chiurchiù et al., 2015). GPR55 expression cytokines after their initial beneficial effects, the immune was increased in the GI tract during sepsis (Lin et al., 2011) system releases several anti-inflammatory mediators, such as IL- and GPR55 knockout mice showed least severe intestinal 10 and IL-1 receptor antagonist and soluble tumor necrosis inflammation in comparison to CB R or CB R knockout 1 2 factor receptors. This begins a cascade of compensatory anti- mice in experimental colitis (Schicho and Storr, 2012). In inflammatory response. Onset of an acute CNS injury also studies using adjuvant-induced inflammation, inflammatory activates immunoinhibitory pathways, leading to a systemic mechanical hyperalgesia by Freund’s complete adjuvant was brain-mediated immunosuppression to minimize secondary absent in GPR55 knockout mice with increased levels of damage to healthy CNS tissue (Meisel et al., 2005; Haeusler et al., IL-4, IL-10, and IFN-g (Staton et al., 2008). Importantly, 2012). Systemic immunosuppression is believed to be the main GPR55 antagonist, CID16020046, diminished inflammation in reason for infections, a leading cause of death in patients with experimental colitis by reducing the levels of pro-inflammatory acute CNS injury. This increased susceptibility to infections, due cytokines, TNF-a, IL-1b, IL-6, and impairing leukocyte activation to impaired immune function after an acute CNS injury, has ˇ ´ and migration (Stancic et al., 2015). In our laboratory, we been termed “CNS injury-induced immunodeficiency syndrome” demonstrated that GPR55 antagonists, CID16020046, and O- (CIDS; Meisel et al., 2005). 1918, reduced LPS-induced leukocyte-endothelial interactions Since the discovery of the ECS, its effects on the brain in experimental models of sepsis in mice (Yang et al., have prompted queries into its potential physiological and 2016b). GPR55 pharmacology with regards to ligand affinity and pathological roles. Local ECS is activated following CNS injury, activity has been controversial in the current literature due to representing an adaptive mechanism. The primary ligands ligand- and concentration-specific biased signaling (Henstridge produced in the brain are anandamide and 2-AG, which work on et al., 2010; Zeng et al., 2015). GPR55 can form heteromers both CB R and CB R. This may play a role in modulation of CNS 1 2 with CB R or CB R to elicit different pathways via ligand- activity and regulation of the immune response after a CNS injury 1 2 and concentration-specific crosstalk (Balenga et al., 2011, 2014; (Mechoulam et al., 1995; Sugiura et al., 1995; Bisogno et al., 1999). Kargl et al., 2012; Martínez-Pinilla et al., 2014). Heteromers There are two different directions for the potential therapeutic of CB R and GPR55 are reported in CNS (Martínez-Pinilla use of CBR: neuroprotection and immunomodulation to reduce et al., 2014) and Human Embryonic Kidney cell lines (Kargl the CNS damage and improve the outcome. et al., 2012). CB R inhibits GPR55 signaling when they are One of the potential ways the brain protects itself is by co-expressed on a cell (Kargl et al., 2012). Cross-interaction reducing its excitatory activity. It is proposed that activation between GPR55 and CB R modulates partner receptor mediated of presynaptic CB R reduces the release of major excitatory 2 1 signaling. Co-expression of CB R with GPR55 reduces GPR55 neurotransmitters, such as glutamate (Coomber et al., 2008), agonist-mediated activation of transcription factors, whereas which might be one of the earliest neuroprotective mechanisms CB2 receptor-mediated signaling was inhibited by co-expression deployed by the brain to prevent excitotoxicity. This is further with GPR55 (Balenga et al., 2014). GPR55-CB R crosstalk supported by studies that showed blocking CB R activity 2 1 in neutrophils was demonstrated by the finding that GPR55 increased the vulnerability of neurons to ischemic damage activation led to augmented neutrophil chemotaxis and reduced and disrupted neuronal maintenance (Schweitzer, 2000; Hwang CB R-mediated tissue injury in the site of inflammation, et al., 2010). Additionally, complete removal of the CB R and 2 1 suggesting a possible cellular mechanism of GPR55-mediated associated signaling pathways causes an increase in susceptibility immune cell modulation (Balenga et al., 2011). Consequently, to ischemic damage, excitotoxin exposure, traumatic brain injury, further investigations on ligand-specific signaling pathways are and exacerbated inflammatory damage (Hillard, 2008). However, Frontiers in Pharmacology | www.frontiersin.org 3 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 4 Zhou et al. Immunomodulation by CB R and GPR55R early inhibition of CB R activation together with increased CB R 2005b). Moreover, monoacylglycerol lipase (MAGL) hydrolyzes 1 2 activation produces beneficial effects, such as a reduction of 2-AG to generate a major arachidonate precursor pool for immune cells in cerebral vasculature, a reduction in infarct size, neuroinflammatory prostaglandins, and is suggested as a and an improved motor function after transient focal ischemia potential drug target in neurodegenerative disease (Nomura (Nagayama et al., 1999; Gilbert et al., 2007; Zhang et al., 2007; et al., 2011; Fernández-Suárez et al., 2014). Although there is no Adhikary et al., 2011). direct evidence suggesting the benefit of MAGL inhibition after The mechanism that may be related to the neuroprotective CNS injury, we can speculate that the involved pathways could aspect of CB signaling is related to ERK in response to tissue be targeted to suppress proinflammatory cascades, which arise insults and involved in cell survival mechanisms (Scotter et al., after an acute CNS injury and contribute to exacerbated CNS 2010). ERK activation is coupled to the presence of CB R in damage. hippocampal regions (Marsicano et al., 2003), suggesting that Due to the changes in the immune status after an acute CB signaling is part of the compensatory response to CNS CNS injury and the onset of CIDS, CB R expression profile injury. Neuronal maintenance aspects of CB signaling seem to on immune cells and other non-neuronal cells suggested a involve MAPK. Experimental support for this notion comes potential theoretical association between the detrimental effects from studies that showed treating the hippocampal tissue with of CNS injury and CB R activity. The immune impairment CB R antagonist AM281 blocked ERK activation through MAPK could potentially be modulated through the activity of the CB R, 1 2 kinase and led to a compromised neuronal survival (Karanian ultimately making the patient susceptible to common infections et al., 2005a). On the other hand, activating the CB R and and worsening the outcome. In general, CB R agonists attenuate 1 2 promoting cell survival also showed the neuroprotective action the inflammatory response by inhibiting production of pro- of the ECS through ERK activity (Jiang et al., 2005). inflammatory mediators, decreasing immune cell chemotaxis Cannabidiol, a main non-psychoactive component of and reducing extravasation in the vulnerable CNS (Shohami cannabis, is suggested to exhibit some of its neuroprotective et al., 2011; Sardinha et al., 2014). Multiple studies have properties via inhibition of EC deactivation or even through its shown CB R activation to be associated with neuroprotection effects on vanilloid and 5-HT receptors (Mishima et al., 2005; and even improved blood brain barrier function (Ramirez Alvarez et al., 2008; Pazos et al., 2013). Other studies have shown et al., 2012). While many studies have established that the that anandamide, 2-AG, THC, and synthetic agonists of CB R CB R activation initiates immunosuppressive mechanisms and 1 2 also exhibit similar neuroprotective effects (Nagayama et al., potentially limits neuroinflammation (Benito et al., 2008), others 1999; Panikashvili et al., 2001). Endogenous anandamide showed have suggested that the time-course of CB R activity may hold neuroprotective properties in the developing brain through the solution by avoiding the negative effects of neuroprotective CB R activity (van der Stelt et al., 2001; Shouman et al., 2006). immunosuppression, while still receiving the neuroprotective Administration of 2-AG to animals with CNS injury reduced aspects of reduced neuroinflammation (Lehmann et al., 2014). brain edema, infarct volume, and hippocampal cell death, and Specifically, it is suggested that the inhibition of CB R that improved behavioral scores, suggesting better recovery (Shohami is done too early could potentially increase the size of et al., 1997; Panikashvili et al., 2006). The excitotoxic protective CNS injury, as the proinflammatory cascades and neutrophil property of ECS activation has been reversed by administration infiltration will continue to develop. In our laboratory, we have of CB R and CB R antagonists, AM281 and AM630, respectively. demonstrated inhibition of CB R by the selective antagonist, 1 2 2 Other CB R antagonists, such as SR-141716A have been shown AM 630, significantly increased immune function as indicated to reduce or completely abolish the neuroprotective properties by an increased leukocyte adherence to endothelia in animals of EC signaling in transient global cerebral ischemia (Nagayama challenged with LPS after hypoxia-ischemia (HI)-induced CNS et al., 1999; Marsicano et al., 2002). Despite piling evidence injury. The CB R inhibition did not affect the magnitude of suggesting the neuroprotective role of ECS, inconsistent results infarct size in the injured brain (Burkovskiy et al., 2016). This and outcomes are produced. The inconsistency is due to various outlines both the complexity of the CNS injury pathology, as well factors, such as the delicacy of the physiological conditions, their as the associated ECS signaling pathways, which remain to be severity, the timing of the pathologic development of a CNS fully explored. injury and the pharmacological intervention. Therefore, careful consideration needs to be given to pharmacological modulation of ECS via CBR in terms of dosage and timing of administration, CONCLUSION otherwise the results may be counterproductive or even harmful. Enhancing EC actions by targeting its degradation represents Although it has been shown that the ECS plays a vital role in the an alternative therapeutic approach and has shown promising function of the immune system, controversial results exist for its results in neuroprotection. The enzyme fatty acid amide regulatory role in sepsis, mainly due to the variety of methods hydrolase (FAAH) is responsible for anandamide breakdown. employed to activate the receptors and the lack of truly selective Pharmacologic inhibition or genetic knockout of FAAH ligands. In addition, in vivo studies using CB R knockout mice promotes neuronal maintenance and function (Hwang et al., showed conflicting results, which might be attributed to the 2010; Celorrio et al., 2016). Block of anandamide transport complexity of the inflammatory models used in mimicking a with AM404 promotes CB R signaling and enhances protection septic state. There is a growing body of evidence for a pro- against excitotoxicity in hippocampal slices (Karanian et al., inflammatory role of GPR55 in sepsis, suggesting that selective Frontiers in Pharmacology | www.frontiersin.org 4 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 5 Zhou et al. Immunomodulation by CB R and GPR55R GPR55 antagonists have a potential as a modulators of the future for this field, potential detrimental effects of ECS immune response, and can be designed as a therapeutic target in modulation need to be studied in more detail to prevent sepsis. unwanted side effects. With regards to the role of the ECS following CNS injury one may feel that cannabinoid signaling entails the “magic bullet” approach to many of the detrimental impairments associated AUTHOR CONTRIBUTIONS with CNS injury. However, not all aspects of cannabinoid signaling have been fully explored and extensive pre-clinical Each author has contributed significantly to this work by testing is essential to find the correct ligand (or combination of writing a section of the manuscript, including its references. JZ: ligands). 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CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation

Zhou, Juan; Burkovskiy, Ian; Yang, Hyewon; Sardinha, Joel; Lehmann, Christian
Frontiers in Pharmacology , Volume 7 – Aug 22, 2016
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fphar-07-00264 August 18, 2016 Time: 16:13 # 1 MINI REVIEW published: 22 August 2016 doi: 10.3389/fphar.2016.00264 CB2 and GPR55 Receptors as Therapeutic Targets for Systemic Immune Dysregulation 1,2 1,3 1,2 1 Juan Zhou , Ian Burkovskiy , Hyewon Yang , Joel Sardinha and 1,2,3 Christian Lehmann 1 2 Department of Anesthesia, Dalhousie University, Halifax, NS, Canada, Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada, Department of Pharmacology, Dalhousie University, Halifax, NS, Canada The endocannabinoid system (ECS) is involved in many physiological processes and has been suggested to play a critical role in the immune response and the central nervous system (CNS). Therefore, ECS modulation has potential therapeutic effects on immune dysfunctional disorders, such as sepsis and CNS injury-induced immunodeficiency syndrome (CIDS). In sepsis, excessive release of pro- and anti-inflammatory mediators results in multi-organ dysfunction, failure, and death. In CIDS, an acute CNS injury dysregulates a normally well-balanced interplay between CNS and the immune system, leading to increased patients’ susceptibility to infections. In this review, we will discuss Edited by: potential therapeutic modulation of the immune response in sepsis and CNS injury by Rukiyah Van Dross-Anderson, manipulation of the ECS representing a novel target for immunotherapy. The Brody School of Medicine at East Carolina University, USA Keywords: endocannabinoid system, immune dysfunction, sepsis, central nervous system injury, Reviewed by: immunosuppression, GPR55, CNS injury-induced immunodeficiency syndrome Rafael Franco, University of Barcelona, Spain Nicholas V. DiPatrizio, INTRODUCTION University of California, Riverside, USA *Correspondence: The endocannabinoid system (ECS) is involved in many physiological processes including Juan Zhou metabolism, inflammation, pain, and neurotransmission (De Petrocellis and Di Marzo, 2009; [email protected] Pandey et al., 2009). It consists of endogenous cannabinoids (EC), cannabinoid receptors (CBR), and EC metabolizing enzymes (De Petrocellis and Di Marzo, 2009; Pertwee et al., 2010). Two Specialty section: major CBRs are identified: CBR type 1 (CB R) and CBR type 2 (CB R; Howlett et al., 2002). CB R 1 2 1 This article was submitted to are mainly expressed in the central nervous system (CNS) and a variety of non-neural peripheral Experimental Pharmacology and Drug tissues, including the vasculature and gut (Pertwee and Ross, 2002). CB R are primarily expressed Discovery, 2 a section of the journal on immune cells but are also identified in selected CNS areas and some peripheral tissues (Klein, Frontiers in Pharmacology 2005). Recently another G protein-coupled receptor, GPR55, has garnered much attention due to its activation by EC and its impact on the immune system (Pertwee, 2007; Yang et al., 2016a). Received: 06 May 2016 Accepted: 05 August 2016 Increasing evidence shows that enhanced EC levels occur during systemic inflammation, such Published: 22 August 2016 as in sepsis or following a CNS injury. Manipulation of the ECS may have therapeutic effects in inflammatory disorders. In this review, we will focus on modulation of CB and GPR55 receptors Citation: 2 Zhou J, Burkovskiy I, Yang H, on immune response in two inflammatory disorders, sepsis, and CNS injury. Both sepsis and CNS Sardinha J and Lehmann C (2016) injury cause the immune system to go through rather rapid and dramatic changes from pro- to anti- CB2 and GPR55 Receptors as inflammatory phases, which may end up costing patients their life. We suggest that the common Therapeutic Targets for Systemic mechanism for modulating and ultimately controlling the response of the immune system can be Immune Dysregulation. achieved through delicate interplay between the endocannabinoid, central nervous and immune Front. Pharmacol. 7:264. systems. doi: 10.3389/fphar.2016.00264 Frontiers in Pharmacology | www.frontiersin.org 1 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 2 Zhou et al. Immunomodulation by CB R and GPR55R et al., 1995; Carrier et al., 2004), while other studies have ECS IN SEPSIS shown inhibitory effects on leukocyte proliferation through the Sepsis is defined as a life-threatening organ dysfunction caused by activation of the CB R (Maresz et al., 2007; Basu and Dittel, 2011). a dysregulated host response to an infection (Singer et al., 2016). This inhibition maybe mediated by CB R-dependent promotion An initial infection with the ensuing systemic inflammatory of apoptosis in dendritic cells, splenocytes, and thymocytes, response becomes amplified, resulting in excessive release of with some diminished activity when CB R antagonists are used both pro- and anti-inflammatory mediators, causing multi-organ (Basu and Dittel, 2011). Additional evidence also supports the dysfunction, failure, and death (Kleinpell et al., 2006; Singer et al., role of CB R in the promotion of apoptosis. For example, 2016). Recently, the ECS has emerged as a potential therapeutic administration of the CB R agonist, JWH-015, induced apoptosis target in sepsis treatment due to its immune modulatory in thymocytes and diminished the proliferative potential of T functions. The effect of modulation of CB R, CB R, and GPR55 cells and B cells (Lombard et al., 2007). Administration of the 1 2 in sepsis-induced systemic inflammation will be described below. CB R antagonist, AM630, showed a reversal of the induction of T cell apoptosis by JWH-133 (another CB R agonist), strongly CB R implicating a CB R dependent mechanism (Singh et al., 2012). 1 2 Cannabinoid receptors type 1 are mainly pre-synaptic receptors This evidence suggests that activation of CB R may promote in axon terminals and their activation causes post-synaptic immune resolution by inducing apoptosis of immune cells, inhibition by preventing neurotransmitter release (Chevaleyre therefore minimizing excessive damage of the pro-inflammatory et al., 2006; Ladak et al., 2011). Manipulating the activity of cascade that occurs early on in sepsis. CB R at critical periods may play a therapeutic role in sepsis. Using an experimental sepsis model, we demonstrated that Studies have suggested that pre-synaptic CB R activation on activation of CB R by the selective CB R agonist, HU308, 1 2 2 autonomic nerves and vascular walls exacerbates the hypotension significantly reduced leukocyte adhesion in the microvasculature associated with septic shock through neurogenic mechanisms (Lehmann et al., 2012). Administration of EC degradation (Godlewski et al., 2004). However, studies using CB R knockout enzyme inhibitors, such as URB597 and JZL184, also decreased mice subjected to endotoxemia showed acute hypotension leukocyte activation in endotoxemic animals (Sardinha et al., indicating that other mechanisms are also responsible for 2014). However, reduced leukocyte activation by JZL184 is hypotension during systemic inflammatory conditions (Bátkai still present in endotoxemic CB R knockout mice, suggesting et al., 2004). In a lipopolysaccharide (LPS) induced experimental that other mechanisms are also involved in the ECS-mediated sepsis model, we demonstrated that inhibition of CB R by its immune regulation in sepsis. antagonist, AM281, significantly reduced leukocyte activation Cytokine production by immune cells plays a critical role and improved intestinal microcirculation (Kianian et al., 2014) in the inflammatory response and can be modulated through and iris microcirculation (Kelly et al., 2010; Al-Banna et al., CB R. Multiple pro-inflammatory cytokines, such as TNF-a, 2013). However, the exact mechanisms of CB R action in sepsis interleukin (IL)-1b, and IL-6, are released in the early stages of and septic shock are not yet completely understood and further the septic cascade. However, activation of the CB R by its agonist studies are still required. HU308 reduced plasma levels of pro-inflammatory cytokines in endotoxemic rats (Lehmann et al., 2012). Administration of the CB R EC, anandamide, decreased the levels of the proinflammatory Cannabinoid receptors type 2 are primarily expressed on immune cytokines IL-12 and IL-23 in vitro in activated microglial cells cells and represent an ideal target for immune modulation (Correa et al., 2009). In addition, T cell activation and release of (Klein, 2005). CB R are G -protein coupled receptors and signal IL-2 were inhibited by administration of the CB R agonist, JWH- 2 i 2 primarily through regulating cAMP levels depending on the 015, and this effect was eliminated by administration of the CB R duration of activation of the receptor (Rinaldi-Carmona et al., antagonist, AM630 (Börner et al., 2009). It was also demonstrated 1998; Börner et al., 2009; Basu and Dittel, 2011). CB R also that activation of CB R by HU308 enhanced the release of 2 2 signal through the mitogen-activated protein kinase (MAPK) IL-10, a prominent anti-inflammatory cytokine, suggesting an pathway by regulating the three major kinases: the extracellular immunosuppressive effect of CB R (Klein, 2005). signal-regulated protein kinases (ERK), p. 38, and c-Jun NH2- terminal kinases (Basu and Dittel, 2011). Both of these major GPR55 signaling pathways play important roles in CB R-mediated GPR55 was initially described as a novel cannabinoid receptor or immune modulating functions including effects on leukocyte putative “CB ” receptor due to its high affinity to cannabinoid activation, migration, proliferation, apoptosis, and cytokine ligands such as 19-THC, 2-AG, anandamide, and rimonabant, production (Basu and Dittel, 2011). In general, CB R activation independent of the presence of CB R and CB R (Sawzdargo 2 1 2 has shown an immune suppressive action, which can be exploited et al., 1999; Begg et al., 2005; Pertwee, 2007; Ryberg et al., for therapeutic benefit in inflammatory diseases such as sepsis. 2007). However, the limited sequence similarity between GPR55 A variety of in vitro studies have shown contradictory results and CBR does not support this concept (Baker et al., 2006). in terms of modulation of the immune response, mainly due Unlike the classical CB R and CB R signaling pathway, GPR55 1 2 to the use of non-selective cannabinoids (Miller and Stella, is coupled to Ga12 and Ga13 proteins, signaling through ras 2008). Some studies have shown that cannabinoids enhanced homolog gene family member A, Rho-associated protein kinase leukocyte proliferation in a dose dependent manner (Derocq and phospholipase C pathway activation. Increased intracellular Frontiers in Pharmacology | www.frontiersin.org 2 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 3 Zhou et al. Immunomodulation by CB R and GPR55R 2C required to develop a specific pharmacological target for precise Ca is followed to activate rhoA, Rac, and cdc42, thereby and designated immune modulation. phosphorylating ERK, resulting in modulation of leukocyte chemotaxis, proliferation, and cytokine production (Ryberg et al., ECS in CNS Injury 2007; Henstridge et al., 2009). Central nervous system injury includes traumatic brain injury, GPR55 is widely expressed in the CNS, immune system, and stroke, cerebral aneurysms, and spinal cord injuries. Survivors peripheral tissues and is involved in many physiological and from acute CNS injury often have complications due to pathophysiological processes (Ryberg et al., 2007; Henstridge infections. The incidence of fatal infections is linked to severity et al., 2011). In the immune system, GPR55 is highly expressed of CNS injury and the status of immune system (Klehmet in the spleen and leukocytes, and its role in the modulation et al., 2009; Shim and Wong, 2016). Following acute CNS of innate and adaptive immune responses suggests a potential injury, cell death occurs at the primary site and cytotoxins are therapeutic effect for sepsis (Staton et al., 2008; Lin et al., released, which trigger significant secondary cell death outside 2011; Schicho and Storr, 2012; Stanci ˇ c ´ et al., 2015). GPR55 acts the original injury area. In addition, function of the blood brain as an essential regulator in innate immunity via stimulatory barrier is impaired, allowing systemic inflammatory mediators effects in neutrophils, mast cells, monocytes, and natural and cells to enter the normally protected CNS tissue, leading killer (NK) cells (Balenga et al., 2011; Cantarella et al., 2011; to the pathology of a CNS injury, i.e., neuroinflammation. Schicho et al., 2011; Chiurchiù et al., 2015). GPR55 on NK The level of neuroinflammation is highly dependent on the cells and monocytes increase pro-inflammatory cytokines, cell severity, duration, and the anatomical context of the CNS cytotoxicity, and decrease monocyte-mediated endocytosis upon injury. To prevent the excessive action of pro-inflammatory activation by LPS (Chiurchiù et al., 2015). GPR55 expression cytokines after their initial beneficial effects, the immune was increased in the GI tract during sepsis (Lin et al., 2011) system releases several anti-inflammatory mediators, such as IL- and GPR55 knockout mice showed least severe intestinal 10 and IL-1 receptor antagonist and soluble tumor necrosis inflammation in comparison to CB R or CB R knockout 1 2 factor receptors. This begins a cascade of compensatory anti- mice in experimental colitis (Schicho and Storr, 2012). In inflammatory response. Onset of an acute CNS injury also studies using adjuvant-induced inflammation, inflammatory activates immunoinhibitory pathways, leading to a systemic mechanical hyperalgesia by Freund’s complete adjuvant was brain-mediated immunosuppression to minimize secondary absent in GPR55 knockout mice with increased levels of damage to healthy CNS tissue (Meisel et al., 2005; Haeusler et al., IL-4, IL-10, and IFN-g (Staton et al., 2008). Importantly, 2012). Systemic immunosuppression is believed to be the main GPR55 antagonist, CID16020046, diminished inflammation in reason for infections, a leading cause of death in patients with experimental colitis by reducing the levels of pro-inflammatory acute CNS injury. This increased susceptibility to infections, due cytokines, TNF-a, IL-1b, IL-6, and impairing leukocyte activation to impaired immune function after an acute CNS injury, has ˇ ´ and migration (Stancic et al., 2015). In our laboratory, we been termed “CNS injury-induced immunodeficiency syndrome” demonstrated that GPR55 antagonists, CID16020046, and O- (CIDS; Meisel et al., 2005). 1918, reduced LPS-induced leukocyte-endothelial interactions Since the discovery of the ECS, its effects on the brain in experimental models of sepsis in mice (Yang et al., have prompted queries into its potential physiological and 2016b). GPR55 pharmacology with regards to ligand affinity and pathological roles. Local ECS is activated following CNS injury, activity has been controversial in the current literature due to representing an adaptive mechanism. The primary ligands ligand- and concentration-specific biased signaling (Henstridge produced in the brain are anandamide and 2-AG, which work on et al., 2010; Zeng et al., 2015). GPR55 can form heteromers both CB R and CB R. This may play a role in modulation of CNS 1 2 with CB R or CB R to elicit different pathways via ligand- activity and regulation of the immune response after a CNS injury 1 2 and concentration-specific crosstalk (Balenga et al., 2011, 2014; (Mechoulam et al., 1995; Sugiura et al., 1995; Bisogno et al., 1999). Kargl et al., 2012; Martínez-Pinilla et al., 2014). Heteromers There are two different directions for the potential therapeutic of CB R and GPR55 are reported in CNS (Martínez-Pinilla use of CBR: neuroprotection and immunomodulation to reduce et al., 2014) and Human Embryonic Kidney cell lines (Kargl the CNS damage and improve the outcome. et al., 2012). CB R inhibits GPR55 signaling when they are One of the potential ways the brain protects itself is by co-expressed on a cell (Kargl et al., 2012). Cross-interaction reducing its excitatory activity. It is proposed that activation between GPR55 and CB R modulates partner receptor mediated of presynaptic CB R reduces the release of major excitatory 2 1 signaling. Co-expression of CB R with GPR55 reduces GPR55 neurotransmitters, such as glutamate (Coomber et al., 2008), agonist-mediated activation of transcription factors, whereas which might be one of the earliest neuroprotective mechanisms CB2 receptor-mediated signaling was inhibited by co-expression deployed by the brain to prevent excitotoxicity. This is further with GPR55 (Balenga et al., 2014). GPR55-CB R crosstalk supported by studies that showed blocking CB R activity 2 1 in neutrophils was demonstrated by the finding that GPR55 increased the vulnerability of neurons to ischemic damage activation led to augmented neutrophil chemotaxis and reduced and disrupted neuronal maintenance (Schweitzer, 2000; Hwang CB R-mediated tissue injury in the site of inflammation, et al., 2010). Additionally, complete removal of the CB R and 2 1 suggesting a possible cellular mechanism of GPR55-mediated associated signaling pathways causes an increase in susceptibility immune cell modulation (Balenga et al., 2011). Consequently, to ischemic damage, excitotoxin exposure, traumatic brain injury, further investigations on ligand-specific signaling pathways are and exacerbated inflammatory damage (Hillard, 2008). However, Frontiers in Pharmacology | www.frontiersin.org 3 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 4 Zhou et al. Immunomodulation by CB R and GPR55R early inhibition of CB R activation together with increased CB R 2005b). Moreover, monoacylglycerol lipase (MAGL) hydrolyzes 1 2 activation produces beneficial effects, such as a reduction of 2-AG to generate a major arachidonate precursor pool for immune cells in cerebral vasculature, a reduction in infarct size, neuroinflammatory prostaglandins, and is suggested as a and an improved motor function after transient focal ischemia potential drug target in neurodegenerative disease (Nomura (Nagayama et al., 1999; Gilbert et al., 2007; Zhang et al., 2007; et al., 2011; Fernández-Suárez et al., 2014). Although there is no Adhikary et al., 2011). direct evidence suggesting the benefit of MAGL inhibition after The mechanism that may be related to the neuroprotective CNS injury, we can speculate that the involved pathways could aspect of CB signaling is related to ERK in response to tissue be targeted to suppress proinflammatory cascades, which arise insults and involved in cell survival mechanisms (Scotter et al., after an acute CNS injury and contribute to exacerbated CNS 2010). ERK activation is coupled to the presence of CB R in damage. hippocampal regions (Marsicano et al., 2003), suggesting that Due to the changes in the immune status after an acute CB signaling is part of the compensatory response to CNS CNS injury and the onset of CIDS, CB R expression profile injury. Neuronal maintenance aspects of CB signaling seem to on immune cells and other non-neuronal cells suggested a involve MAPK. Experimental support for this notion comes potential theoretical association between the detrimental effects from studies that showed treating the hippocampal tissue with of CNS injury and CB R activity. The immune impairment CB R antagonist AM281 blocked ERK activation through MAPK could potentially be modulated through the activity of the CB R, 1 2 kinase and led to a compromised neuronal survival (Karanian ultimately making the patient susceptible to common infections et al., 2005a). On the other hand, activating the CB R and and worsening the outcome. In general, CB R agonists attenuate 1 2 promoting cell survival also showed the neuroprotective action the inflammatory response by inhibiting production of pro- of the ECS through ERK activity (Jiang et al., 2005). inflammatory mediators, decreasing immune cell chemotaxis Cannabidiol, a main non-psychoactive component of and reducing extravasation in the vulnerable CNS (Shohami cannabis, is suggested to exhibit some of its neuroprotective et al., 2011; Sardinha et al., 2014). Multiple studies have properties via inhibition of EC deactivation or even through its shown CB R activation to be associated with neuroprotection effects on vanilloid and 5-HT receptors (Mishima et al., 2005; and even improved blood brain barrier function (Ramirez Alvarez et al., 2008; Pazos et al., 2013). Other studies have shown et al., 2012). While many studies have established that the that anandamide, 2-AG, THC, and synthetic agonists of CB R CB R activation initiates immunosuppressive mechanisms and 1 2 also exhibit similar neuroprotective effects (Nagayama et al., potentially limits neuroinflammation (Benito et al., 2008), others 1999; Panikashvili et al., 2001). Endogenous anandamide showed have suggested that the time-course of CB R activity may hold neuroprotective properties in the developing brain through the solution by avoiding the negative effects of neuroprotective CB R activity (van der Stelt et al., 2001; Shouman et al., 2006). immunosuppression, while still receiving the neuroprotective Administration of 2-AG to animals with CNS injury reduced aspects of reduced neuroinflammation (Lehmann et al., 2014). brain edema, infarct volume, and hippocampal cell death, and Specifically, it is suggested that the inhibition of CB R that improved behavioral scores, suggesting better recovery (Shohami is done too early could potentially increase the size of et al., 1997; Panikashvili et al., 2006). The excitotoxic protective CNS injury, as the proinflammatory cascades and neutrophil property of ECS activation has been reversed by administration infiltration will continue to develop. In our laboratory, we have of CB R and CB R antagonists, AM281 and AM630, respectively. demonstrated inhibition of CB R by the selective antagonist, 1 2 2 Other CB R antagonists, such as SR-141716A have been shown AM 630, significantly increased immune function as indicated to reduce or completely abolish the neuroprotective properties by an increased leukocyte adherence to endothelia in animals of EC signaling in transient global cerebral ischemia (Nagayama challenged with LPS after hypoxia-ischemia (HI)-induced CNS et al., 1999; Marsicano et al., 2002). Despite piling evidence injury. The CB R inhibition did not affect the magnitude of suggesting the neuroprotective role of ECS, inconsistent results infarct size in the injured brain (Burkovskiy et al., 2016). This and outcomes are produced. The inconsistency is due to various outlines both the complexity of the CNS injury pathology, as well factors, such as the delicacy of the physiological conditions, their as the associated ECS signaling pathways, which remain to be severity, the timing of the pathologic development of a CNS fully explored. injury and the pharmacological intervention. Therefore, careful consideration needs to be given to pharmacological modulation of ECS via CBR in terms of dosage and timing of administration, CONCLUSION otherwise the results may be counterproductive or even harmful. Enhancing EC actions by targeting its degradation represents Although it has been shown that the ECS plays a vital role in the an alternative therapeutic approach and has shown promising function of the immune system, controversial results exist for its results in neuroprotection. The enzyme fatty acid amide regulatory role in sepsis, mainly due to the variety of methods hydrolase (FAAH) is responsible for anandamide breakdown. employed to activate the receptors and the lack of truly selective Pharmacologic inhibition or genetic knockout of FAAH ligands. In addition, in vivo studies using CB R knockout mice promotes neuronal maintenance and function (Hwang et al., showed conflicting results, which might be attributed to the 2010; Celorrio et al., 2016). Block of anandamide transport complexity of the inflammatory models used in mimicking a with AM404 promotes CB R signaling and enhances protection septic state. There is a growing body of evidence for a pro- against excitotoxicity in hippocampal slices (Karanian et al., inflammatory role of GPR55 in sepsis, suggesting that selective Frontiers in Pharmacology | www.frontiersin.org 4 August 2016 | Volume 7 | Article 264 fphar-07-00264 August 18, 2016 Time: 16:13 # 5 Zhou et al. Immunomodulation by CB R and GPR55R GPR55 antagonists have a potential as a modulators of the future for this field, potential detrimental effects of ECS immune response, and can be designed as a therapeutic target in modulation need to be studied in more detail to prevent sepsis. unwanted side effects. With regards to the role of the ECS following CNS injury one may feel that cannabinoid signaling entails the “magic bullet” approach to many of the detrimental impairments associated AUTHOR CONTRIBUTIONS with CNS injury. However, not all aspects of cannabinoid signaling have been fully explored and extensive pre-clinical Each author has contributed significantly to this work by testing is essential to find the correct ligand (or combination of writing a section of the manuscript, including its references. JZ: ligands). 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