Neuroinflammation is defined as inflammation of the nervous tissue. This inflammation may be initiated in response to a wide variety of stimuli, including infections, autoimmune or neurodegenerative disorders, traumatic brain injury, or stress. In the central nervous system, which was regarded as an immunologically privileged site because of the presence of the protective blood-brain barrier (composed of astrocytes and endothelial cells), immune functions are mediated by microglia, the resident innate immune cells, as well as by infiltrating immune cells. Although the neuroinflammatory response is initiated to exert protective effects, it may also exert detrimental effects and cause widespread inflammation through the blood-brain barrier. In fact, circulating peripheral immune cells may bypass an altered blood-brain barrier and come into contact with neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the peripheral immune response. Even more, innate immune molecules such as complement proteins and cytokines regulate synaptic plasticity and neurogenesis, whereas amyloid-β and α-synuclein, biomarkers of neurodegenerative diseases, have antimicrobial roles. Type I interferons, for example, seem critical for normal neuronal homeostasis as a regulator of autophagy-mediated protein degradation, and T-cell cytokines IFN-g and IL-4 are involved in social and cognitive behavior. These findings suggest that, depending on the pathogen, host genotype or environmental factors, both pathogen and antipathogen pathways may affect interneuronal communication, leading to adaptive or maladaptive effects on brain function.1 Thus, microglia is associated with clearance of cellular debris and toxicants, neurogenesis, and anti-inflammatory response, as well as synaptic monitoring and pruning. In turn, neurons play an important role in microglia function, by maintaining inflammatory gene production, oxidative stress response, and phagocytosis at an appropriate level, in order to keep their own homeostasis under normal physiological conditions. However, both neurons and microglia are sensitive to psychosocial stress, and chronic stress may impair the dynamic balance of neuron-microglia interaction, disturb synaptic neurotransmission, and thus increase the susceptibility to mental disorders. Similarly, aging also potentiates oxidative stress and neuroinflammation, leading to disturbances in synaptic monitoring and pruning functions, notably through defective phagocytosis.2 Therefore, microglia has gradually emerged as a key interface between stress-related signals and neuroimmune consequences of stress, with different stressors leading to elevated microglial activity. The hippocampus and prefrontal cortex areas are especially involved.3

In psychiatric diseases such as mood disorders or schizophrenia, the inflammatory response system is activated4 (see also Müller, in this issue p 55). The majority of studies have focused on antibodies, cytokines, and blood cell types (see also the rest of this issue). In addition, many epidemiological studies have implicated immune mechanisms as risk factors for developing schizophrenia: large odds ratios were reported for season of birth, maternal viral infection, cytokine alterations, and antibody/viral titer.5 Accordingly, during the last decade, anti-inflammatory therapeutic approaches have been studied in schizophrenia and depression.

An extensive recent review of genetics in schizophrenia concluded that the most consistent result throughout the genome-wide association studies of schizophrenia is the association to the extended major histocompatibility complex locus located on chromosome 6p21.3 (MHC) or human leukocyte antigen (HLA) system.6 This broad region comprises at least 121 functional genes. Significant MHC single-nucleotide polymorphisms associated, not only with schizophrenia, but also with bipolar disorder, cognition, or hippocampal volume have been reported.7 Even more surprising, immune-mediated brain anomalies can be transmitted to subsequent generations providing interesting research avenues.8

Finally, Felger et al9 have shown that an increase in inflammation, as demonstrated by plasma CRP and inflammatory cytokines, was associated with decreased connectivity within reward-related brain regions in unmedicated outpatients with major depression. In their study, decreased connectivity between ventral striatum and ventromedial prefrontal cortex (vmPFC) was correlated with symptoms of anhedonia, whereas decreased connectivity between dorsal striatum and vmPFC correlated with psychomotor slowing. Interestingly, in non-human primates, chronic administration of inflammatory cytokines decreased striatal dopamine release, as measured by translational neuroimaging and in vivo microdialysis.10

This issue will focus on the intriguing interplay between neuroinflammation and neuropsychiatric diseases.