Abstract
Increased cytokine and inflammatory-related transcripts are found in the ventral midbrain, a dopamine neuron-rich region associated with schizophrenia symptoms. In fact, half of schizophrenia cases can be defined as having a “high inflammatory/immune biotype.” Recent studies implicate both complement and macrophages in cortical neuroinflammation in schizophrenia. Our aim was to determine whether measures of transcripts related to phagocytosis/macrophages (CD163, CD64, and FN1), or related to macrophage adhesion [intercellular adhesion molecule 1 (ICAM1)], or whether CD163+ cell density, as well as protein and/or gene expression of complement pathway activators (C1qA) and mediators (C3 or C4), are increased in the midbrain in schizophrenia, especially in those with a high inflammatory biotype. We investigated whether complement mRNA levels correlate with macrophage and/or microglia and/or astrocyte markers. We found CD163+ cells around blood vessels and in the parenchyma and increases in ICAM1, CD163, CD64, and FN1 mRNAs as well as increases in all complement transcripts in the midbrain of schizophrenia cases with high inflammation. While we found positive correlations between complement transcripts (C1qA and C3) and microglia or astrocyte markers across diagnostic and inflammatory subgroups, the only unique strong positive correlation was between CD163 and C1qA mRNAs in schizophrenia cases with high inflammation. Our study is the first to suggest that more circulating macrophages may be attracted to the midbrain in schizophrenia, and that increased macrophages are linked to increased complement pathway activation in tissue and may contribute to dopamine dysregulation in schizophrenia. Single-cell transcriptomic studies and mechanistic preclinical studies are required to test these possibilities.
Highlights
Dopaminergic dysregulation is at the core of schizophrenia symptoms, and includes subcortical hyperdopaminergia, underlying psychosis, and frontal hypodopaminergia, contributing to cognitive deficits [1, 2]
We found that intercellular adhesion molecule 1 (ICAM1) mRNA was increased by 123.3% in the midbrain when all schizophrenia cases were compared to controls (t = −5.25, df = 40.40, p < 0.0001) (Figure 1A)
We provide the first evidence of increased macrophage markers and macrophage density proximal to dopamine cell bodies in schizophrenia, compared to controls, which is especially robust in a subset of schizophrenia cases with a high inflammatory biotype compared to controls
Summary
Dopaminergic dysregulation is at the core of schizophrenia symptoms, and includes subcortical hyperdopaminergia, underlying psychosis, and frontal hypodopaminergia, contributing to cognitive deficits [1, 2]. Neuropathology is evident at the molecular and neurotransmitter level within the ventral midbrain of people with schizophrenia [3,4,5,6,7,8], the region where the majority of dopamine cell bodies are found. Increases in pro-inflammatory cytokines and gliosis [9] are some of the most robust pathological changes found in the midbrain of people with schizophrenia to date; the inflammatory mechanisms of midbrain inflammation that may contribute to dopamine dysregulation in patients are poorly understood. High levels of inflammation are linked to more severe symptoms, greater neuropathology, and exacerbated cognitive deficits [e.g., [11, 18, 19, 21,22,23,24]]. Increased tissue inflammation can lead to increases in phagocytosis-primed macrophages in neurological disease and following brain injury [25,26,27]; we expect to find increased macrophages and higher complement production in the midbrain of those with schizophrenia, increased cytokines and gliosis [9]
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