Abstract
BackgroundAtypical antipsychotic agents, such as clozapine, are used to treat schizophrenia and other psychiatric disorders by a mechanism that is believed to involve modulating the immune system. Multiple sclerosis is an immune-mediated neurological disease, and recently, clozapine was shown to reduce disease severity in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). However, the mode of action by which clozapine reduces disease in this model is poorly understood.MethodsBecause the mode of action by which clozapine reduces neuroinflammation is poorly understood, we used the EAE model to elucidate the in vivo and in vitro effects of clozapine.ResultsIn this study, we report that clozapine treatment reduced the infiltration of peripheral immune cells into the central nervous system (CNS) and that this correlated with reduced expression of the chemokines CCL2 and CCL5 transcripts in the brain and spinal cord. We assessed to what extent immune cell populations were affected by clozapine treatment and we found that clozapine targets the expression of chemokines by macrophages and primary microglia. Furthermore, in addition to decreasing CNS infiltration by reducing chemokine expression, we found that clozapine directly inhibits chemokine-induced migration of immune cells. This direct target on the immune cells was not mediated by a change in receptor expression on the immune cell surface but by decreasing downstream signaling via these receptors leading to a reduced migration.ConclusionsTaken together, our study indicates that clozapine protects against EAE by two different mechanisms; first, by reducing the chemoattractant proteins in the CNS; and second, by direct targeting the migration potential of peripheral immune cells.
Highlights
Atypical antipsychotic agents, such as clozapine, are used to treat schizophrenia and other psychiatric disorders by a mechanism that is believed to involve modulating the immune system
To understand if clozapine altered the early infiltration of immune cells into the central nervous systems (CNS) post immunization, female C57BL/6 mice were treated with clozapine or vehicle commencing 1 day prior to immunization throughout the whole course of the experiment and the number and type of immune cells in the spinal cord and brain were analyzed by flow cytometry 5, 7, 9, and 11 days after EAE induction (Additional file 5: Figure S5a,b).)
These results indicate that clozapine reduces the infiltration of monocytes, neutrophils, and T cells pre and post disease onset
Summary
Atypical antipsychotic agents, such as clozapine, are used to treat schizophrenia and other psychiatric disorders by a mechanism that is believed to involve modulating the immune system. Migration of activated leukocytes and macrophages is controlled by several different proinflammatory chemotactic cytokines, called chemokines [11]. These are produced and released locally and diffuse into the bloodstream thereby attracting leukocytes to the site of inflammation. Monocyte chemoattractant protein 1 (MCP1) or CCL2 and regulated upon activation normal T cell expressed and secreted (RANTES) or CCL5 belong to the family of C-C chemokines involved in the recruitment of monocytes, macrophages, and activated lymphocytes to the site of expression [12] and mediate leukocyte adhesion to epithelial cells [13]. CCL2 and CCL5 are expressed by a wide array of different cell types constitutively within the CNS or secreted by infiltrating blood-derived macrophages upon their migration into the CNS. Drugs that would target CCL2 and CCL5 expression directly would be highly beneficial
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