Cannabinoid receptors on peripheral leukocytes from patients with schizophrenia: Evidence for defective immunomodulatory mechanisms
Introduction
Schizophrenia is a severe psychiatric syndrome of unknown etiology. Despite the great progress in the past years, much is still to be elucidated about what causes schizophrenia and how to treat it effectively (Owen et al., 2016). Schizophrenia seems to be caused by genetic or environmental factors, or both. Among several factors that might be involved in its pathogenesis, the immune system has been extensively studied (Miller et al., 2011, Potvin et al., 2008). Reports of altered expression of immune-related genes, changes in the levels of cytokines, antibodies and immune response-related cells point toward an immune dysfunction in schizophrenia (Sperner-Unterweger and Fuchs, 2015). The basis for this immune dysfunction in patients with schizophrenia remains largely unknown, although environmental triggers such as stress, smoking and substance abuse are known to influence inflammatory pathways (Berk et al., 2013).
Cannabis use is one of the most important and studied environmental risk factors related to psychosis (Andréasson et al., 1987). Acute cannabis intoxication may produce symptoms resembling psychosis, while chronic use is associated with negative symptoms (D'Souza et al., 2004, Sewell et al., 2009, Spano et al., 2010). Not only cannabis use has been linked to schizophrenia development, but the endocannabinoid system (ES) has also been implicated in the pathogenesis of the syndrome (Giuffrida et al., 2004, Koethe et al., 2009). The ES comprises the receptors cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R), several endogenous ligands collectively called endogenous cannabinoids or endocannabinoids (eCBs), and enzymes responsible for the synthesis and catabolism of eCBs (Howlett et al., 2002, Pertwee et al., 2010). Cannabinoid receptors (CBRs) are widely distributed in brain areas implicated in the pathogenesis of psychotic symptoms such as the prefrontal cortex, hippocampus, and basal nuclei (D'Souza et al., 2004). Increased levels of the eCB anandamide were reported in the cerebrospinal fluid of patients with schizophrenia (Koethe et al., 2009). Apart from the central nervous system, studies have described peripheral changes in CBRs in patients with schizophrenia. Increased expression of CBRs on lymphocytes and monocytes was significantly correlated with impaired cognitive performance (Ferretjans et al., 2014). More evidence was provided by genetic studies, since polymorphisms in the CB1R gene have been implicated in susceptibility to schizophrenia (Ujike et al., 2002).
Besides their neuromodulatory effects, cannabinoids may play several immune roles. In the periphery, they modulate hematopoiesis, platelet aggregation, increase regulatory T-cells, as well as chemokine release and migration of immunocompetent cells (De Marchi et al., 2003). They thus have impacts on both the innate and adaptive immune systems. The former consists of invariantly present cells and proteins including neutrophils, natural killer (NK) cells, and circulating plasma proteins. The adaptive immune system includes cell-mediated immunity that is mediated by T-cells and humoral immunity that is mediated by antibodies produced by B-cells. In the CNS, cannabinoids can reduce neuroinflammation by inhibiting Th1 response (Katona et al., 2005).
This study aimed to evaluate CBRs expression on peripheral immune response-related cells, i.e., blood monocytes, neutrophils, lymphocytes, and NK-cells, and their relationship to a wide range of serum cytokine levels in subjects with schizophrenia and controls. We hypothesized that the ES may be disrupted in the periphery (i.e. blood) of patients with schizophrenia, being associated with the immune/inflammatory changes present in this illness.
Section snippets
Subjects
A sample of 55 patients with chronic schizophrenia was recruited from the Schizophrenia Outpatient Clinic, Raul Soares Institute/FHEMIG, Belo Horizonte-MG, Brazil. Diagnosis was confirmed by the MINI-Plus interview (Amorim et al., 1998) using DSM-IV TR criteria (APA, 2000). We included only clinical stable patients (see criteria below) aged between 18 and 60 years old. In addition, a group of 48 subjects with no current psychiatric disorder was included as controls. Control individuals were
Demographic and clinical data
Demographic and clinical data are shown in Table 1. Schizophrenic patients and controls did not differ regarding age and gender. Patients with schizophrenia presented 15 years of mean disease length. All patients were currently using antipsychotic drugs.
Cannabinoid receptors (CB1R and CB2R) expression on immune response-related cells
Patients with schizophrenia presented increased expression of both CB1R and CB2R on neutrophils (p < 0.05) and monocytes (p < 0.05), and higher CB2R expression on NK-cells (p < 0.01) when compared with controls (Fig. 1). Patients with
Discussion
To the best of our knowledge, this is the first study to evaluate the association between CBRs expression on immune response-related cells and circulating levels of cytokines in patients with schizophrenia. In addition to changes in peripheral ES and circulating cytokines in schizophrenia, we found that patients showed a poor correlation network between cytokines and expression of CBR receptors.
Several studies have described ES alterations in schizophrenia (De Marchi et al., 2003, Ortega-Alvaro
Conflicts of interest
The authors report no conflict of interest.
Contributors
SMCC participated in the design, data collection and interpretation of biological measures, and drafted the first version of the manuscript. MSA, ACOS, VBR ATC and OAMF participated in the design, data collection and interpretation of biological measures. RF and RRS participated in subject recruitment, clinical data collection and interpretation. NPR, MB, JVS and ALT were responsible for the study design, all data interpretation, and writing the manuscript. All authors read, revised and
Role of funding source
This study was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Centro de Pesquisas René Rachou (CPqRR) da Fundação Oswaldo Cruz (FIOCRUZ). MB is supported by a NHMRC Senior Principal Research Fellowship 1059660. Funders had no involvement in study design, collection, analysis and interpretation of data, writing
Acknowledgments
Authors would like to thank the participation of volunteers in this study and are indebted to their caregivers for their magnificent support. This study was supported by grants from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Centro de Pesquisas René Rachou (CPqRR) da Fundação Oswaldo Cruz (FIOCRUZ). MB is supported by a NHMRC
References (45)
- et al.
Dsm-IH-R psychotic disorders: procedural validity of the Mini International Neuropsychiatric interview (MINI). Concordance and causes for discordance with the CIDI
Eur. Psychiatry
(1998) - et al.
Cannabis and schizophrenia. A longitudinal study of Swedish conscripts
Lancet
(1987) - et al.
Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia
J. Psychiatr. Res.
(2013) - et al.
Increased level of serum cytokines, chemokines and adipokines in patients with schizophrenia is associated with disease and metabolic syndrome
Psychoneuroendocrinology
(2012) - et al.
Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use
Neuroscience
(2001) - et al.
Anandamide and Delta9-tetrahydrocannabinol directly inhibit cells of the immune system via CB2 receptors
J. Neuroimmunol.
(2007) - et al.
Cognitive performance and peripheral endocannabinoid system receptor expression in schizophrenia
Schizophr. Res.
(2014) - et al.
Regulation of CCL2/MCP-1 production in astrocytes by desipramine and atomoxetine: involvement of α2 adrenergic receptors
Brain Res. Bull.
(2011) - et al.
Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects
Biol. Psychiatry
(2011) - et al.
Inflammatory cytokines alterations in schizophrenia: a systematic quantitative review
Biol. Psychiatr.
(2008)