Role of microglial m1/m2 polarization in relapse and remission of psychiatric disorders and diseases

Abstract

Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed that M1/M2 polarization of macrophages plays an important role in controlling the balance between promotion and suppression in inflammation. Microglial cells share certain characteristics with macrophages and contribute to immune-surveillance in the central nervous system (CNS). In this review, we summarize immunoregulatory functions of microglia and discuss a possible role of microglial M1/M2 polarization in relapse and remission of psychiatric disorders and diseases. M1 polarized microglia can produce pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, suggesting that these molecules contribute to dysfunction of neural network in the CNS. Alternatively, M2 polarized microglia express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. Based on these aspects, we propose a possibility that M1 and M2 microglia are related to relapse and remission, respectively in psychiatric disorders and diseases. Consequently, a target molecule skewing M2 polarization of microglia may provide beneficial therapies for these disorders and diseases in the CNS.

Figure 1

M1/M2 polarization of microglia and their immunoregulatory functions. Resting microglial cells are stimulated with PAMPS or DAMPS via TLR or ATP receptors. In the presence of LPS and IFN-γ, microglial cells polarize to M1 phenotype and produce pro-inflammatory cytokines/mediators including IL-1β, IL-6, TNF-α, CCL2, ROS, and NO. In contrast, IL-4 and IL-13 induce alternative activation of microglia to M2 (‘M2a’) phenotype which down-regulates M1 functions by anti-inflammatory cytokine, IL-10.

Figure 2

Hypothetical model of relationship between M1/M2 microglia activities and symptom severity in schizophrenia. (A) In the early stage of schizophrenia, symptoms may be followed by microglial M1 polarization which is induced by neuronal hyperactivation in insula, inferior frontal gyrus, and hippocampus, possible initiating brain regions of the disorder. M1 microglia can produce pro-inflammatory cytokines and remove the damaged nerve fibers by phagocytosis, whereas M2 microglia down-regulate M1 microglial function and restore tissue homeostasis with consequent attenuation of symptoms. (B) If M2 polarization of microglia is insufficient, M1 microglial functions are maintained and induce neural network dysfunctions continuously. Symptom severity may gradually become high according to the frequency of M1 polarization.

Figure 3

Possible roles of M1/M2 microglia in neural network functions, activities of monoamine neurons, and symptoms in major depressive disorder. In healthy individuals, prefrontal cortex regulates neural circuitry of mood including amygdala and dopamine neurons projecting from VTA (ventral tegmental area) to NAc (nucleus accumbens) (1, 2). In patients with major depressive disorder, hyperactivation of neural circuitry induces M1 polarization of microglia (3), resulting in dysfunction of nerve fibers between prefrontal cortex and the neural circuitry (4) and hypoactivation of 5-HT neurons projecting from raphe nucleus to prefrontal cortex (5). Dysfunction of prefrontal cortex can reduce activity of dopamine neurons projecting from VTA to NAc (6). Hypoactivation of prefrontal cortex and NAc are associated with depressed mood and loss of interest/pleasure, respectively. M2 microglia restore homeostasis of nerve fibers and 5-HT biosynthesis, recovering dysfunction of prefrontal cortex and NAc (7, 8).

Figure 4

Possible roles of the cannabinoid receptors in M1/M2 polarization of microglia. 2-AG released from M1 microglia promotes production of pro-inflammatory cytokines and mediators by M1 microglia via CB₁ and then induces down-regulation of CB₁. On the other hand, 2-AG stimulates M2 polarization of microglia via CB₂. Subsequently, M2 microglia can produce IL-10 and anti-inflammatory/pro-resolving lipid mediators (resolvin D1 and lipoxin A4).