The neuroinflammatory basis of schizophrenia and bipolar disorder: spotlight on brain macrophages, cytokines, and the blood-brain barrier

Abstract

Schizophrenia is a severe mental disorder that has been associated with dysregulation of the immune system. Using inflammatory cytokine transcript levels, we found approximately 40% of individuals with schizophrenia are classified as having elevated levels of inflammation with worse neuropathology. The aim of this study was to investigate the extent to which neuroinflammation is associated with schizophrenia in the dorsolateral prefrontal cortex (DLPFC) and midbrain. We used postmortem human brain tissue to investigate multiple inflammation-related molecular mechanisms. First, in the DLPFC, we found macrophages and astrocytes, rather than microglia, contributed more to neuroinflammation in schizophrenia, by showing unchanged or decreased microglial markers and elevated macrophage markers. Macrophage marker expression was more related to pro-inflammatory marker and macrophage recruitment chemokine expression. In addition, we classified "high" and "low" inflammatory (HI and LI) subgroups using inflammatory cytokine and macrophage marker protein levels as discriminators in the DLPFC for the first time. 30% of controls (CTRL) and 56% schizophrenia (SCZ) cases were classified as high inflammation individuals. We found higher CD163+ macrophage density in the DLPFC of SCZ-HI subgroup mainly around small blood vessels of both grey and white matter. In the midbrain, we characterized a substantial proportion of individuals in schizophrenia (46%) and bipolar disorder (29%) expressing elevated inflammatory mRNA (IL6, IL1, TNF and SERPINA3), which were termed the "high" inflammatory (HI) subgroups, and we confirmed increases in IL6 and IL1 at the protein level in these subgroups. Furthermore, we showed elevated macrophage and chemokine marker expression in schizophrenia and bipolar disorder HI subgroups which were associated with changed blood-brain barrier markers, indicating potential macrophage transmigration, supported by altered mRNA and protein levels in the adhesion molecules, tight junction proteins, basement membrane proteins, and angiogenic factors related to blood vessel regulation. Importantly, we observed a novel but unknown neuropathology of more frequent claudin-5 "cell bursts" between blood vessel fragments in schizophrenia and bipolar high inflammatory subgroups. These findings have implications for new immune-related treatments, therapy development, and potential targets for measuring disease progression or early detection of schizophrenia and bipolar disorder.