Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia

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.

The Protein-Protein Interaction Network of First Episode Psychosis and Schizophrenia Reveals Possible Trigger Factors and New Drug Targets among Intracellular Signal Transduction Pathways and Neurotoxicity Processes

“…The involvement of complement in FEP/FES agrees with previous findings showing increased plasma C3C and C4, and CSF and brain C4 complement factors in schizophrenia [2,75,76]. Moreover, increased C1qA, C3, and C4 transcripts were reported to be associated with microglial activation in the midbrain of schizophrenia patients [77]. It should be added that FES is accompanied by increased formation of the IgA C1qA CIC, which may have detrimental effects in its own right [7].…”

Cryptococcus neoformans-Infected Macrophages Release Proinflammatory Extracellular Vesicles: Insight into Their Components by Multi-omics

“…Additionally, the proinflammatory effects of EVs may also be caused by host components. Among the top core EV proteins in all these EVs, the most enriched protein, Fn1, also known as an alarmin in macrophage EVs, was associated with inflammatory disease ( 34 , 39 ), followed by Hspg2, which was reported to regulate an NF-κB-mediated pathway ( 40 ). SM(d18:1/16:0), the most enriched core EV lipid, increased cell ATP production through enhanced aerobic glycolysis ( 41 ).…”

Reductions in midbrain GABAergic and dopamine neuron markers are linked in schizophrenia

“…The decrease in GABRA3 mRNA was the only change that was consistent with our hypothesis that GABA deficits would be most pronounced in cases with a high inflammatory biotype. We previously established that the midbrain is a site of convergence of macrophage presence, microglial activation, and enhanced activity of the complement cascade [ 54 , 55 ], and the convergence of these inflammatory processes may lead to disruption of neurotransmitter systems within the midbrain. It is possible that a global deficit in GABAergic neurotransmission and a heightened state of neuroinflammation in the midbrain coalesce to impact the GABRA3-expressing dopaminergic neurons of the nigrostriatal pathway, although mechanistic studies are needed to test this hypothesis.…”

“…Neuroinflammation is implicated in the pathophysiology of schizophrenia and is linked to inhibitory interneuron deficits in the cortex [ 47 – 53 ]. We recently identified heightened neuroinflammation in the midbrain of people with schizophrenia [ 54 , 55 ]. Gene expression of inflammatory markers, particularly IL1B , IL6 , SERPINA3 (and TNFA in midbrain), are used to identify schizophrenia cases with ‘low’ and ‘high’ inflammatory biotypes [ 50 , 51 , 54 , 56 , 57 ].…”