Cannabinoid receptors on peripheral leukocytes from patients with schizophrenia: Evidence for defective immunomodulatory mechanisms

Abstract

Objectives

to evaluate cannabinoid receptors (CBRs) expression on peripheral immune 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.

Methods

A sample of 55 people with chronic schizophrenia and 48 controls were enrolled in the study. The expression of the cannabinoid receptors CB1R and CB2R was evaluated in peripheral blood leukocytes by flow cytometry. Serum levels of cytokines/chemokines were simultaneously analyzed by cytometric bead array.

Results

We found higher expression of cannabinoid receptors on cells of the innate immune system in subjects with schizophrenia when compared with controls. Serum levels of interleukin-4 (IL-4), IL-6, IL-10, IL-17, interferon (IFN-γ), and (C-X-C motif) ligand 10/interferon gamma-induced protein 10 (CXCL10/IP10) were decreased, while levels of the chemokine (C-C motif) ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were increased in the schizophrenia group in comparison with controls. Patients with schizophrenia showed simpler correlation network between cytokines and CBRs expression than controls.

Conclusion

Patients with schizophrenia showed increased CBRs expression in cells of the innate immune system and simpler correlation network between cytokines and CBRs expression when compared with controls. These results suggest a defective endocannabinoid system-mediated immunomodulation in patients with schizophrenia.

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.