CD163+ perivascular macrophages in schizophrenia: a research framework for testing macrophage-related mechanisms
Hans C Klein1,2, Paul C Guest3,4,5, Michael E Benros6
1Department of Nuclear Medicine and Molecular Imaging, University of Groningen, Groningen, Netherlands.
Abstract:
Elevated densities of CD163+ perivascular macrophages have been reported in schizophrenia post-mortem brain tissue, particularly in regions involved in neurodevelopment, dopaminergic signaling, and blood-brain barrier (BBB) regulation. However, the biological significance and developmental lineage of these findings remain unclear. While CD163 is linked to regulatory and scavenging functions, macrophage activation states form a continuum and cannot be inferred from any single marker. This Perspective outlines a structured, testable research framework to determine whether this accumulation reflects altered responsiveness to persistent intracellular, inflammatory, systemic, or treatment-related signals. To test this, we propose sequential methodological aims, including defining CD163+ cell localization and phenotypes in predefined brain regions, and assessing viral and non-viral molecular signals using spatial transcriptomic and cell-specific methods. This framework also involves comparing macrophage activation states across schizophrenia and other psychiatric and non-psychiatric control groups, using single-cell and single-nucleus sequencing. By not presuming a specific infectious aetiology, this approach will provide a general methodology to investigate macrophage-related mechanisms across diverse potential triggers. Within this model, HSV-1 is evaluated strictly as an illustrative proof-of-concept candidate for testing intracellular pathogen responses, rather than an exclusive cause, as epidemiological associations have been inconsistent and localization of viral materials within these cells has not been demonstrated. Similarly, Bacille Calmette-Guérin (BCG)-associated trained immunity is introduced strictly as a preliminary, ex vivo/in vitro approach to probe macrophage reprogramming and plasticity. Ultimately, this framework provides a systematic approach for investigating macrophage-related mechanisms and their potential drivers in schizophrenia without presupposing a specific underlying aetiology.
Insights
Schizophrenia brain tissue shows increased CD163+ macrophages, crucial for neurodevelopment and blood-brain barrier function. This research framework investigates their role and potential triggers without assuming a specific cause.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Elevated CD163+ perivascular macrophages observed in schizophrenia brain tissue, particularly in key functional regions.
- The biological significance and origin of these macrophages remain undetermined.
- CD163's role in macrophage function is complex, and single markers don't define activation states.
Purpose of the Study:
- To establish a structured research framework for investigating CD163+ macrophage accumulation in schizophrenia.
- To determine if this accumulation results from altered responses to various signals (intracellular, inflammatory, systemic, treatment-related).
- To provide a general methodology for studying macrophage mechanisms in schizophrenia without presupposing a specific etiology.
Main Methods:
- Define CD163+ cell localization and phenotypes in specific brain regions.
- Assess molecular signals using spatial transcriptomics and cell-specific methods.
- Compare macrophage activation states across schizophrenia and control groups using single-cell and single-nucleus sequencing.
Main Results:
- The proposed framework allows for systematic investigation of macrophage roles and potential drivers in schizophrenia.
- It enables testing of various hypotheses regarding macrophage activation and responsiveness.
- The approach is adaptable for studying diverse potential triggers, including intracellular pathogens and trained immunity.
Conclusions:
- This systematic framework offers a novel approach to understanding macrophage-related mechanisms in schizophrenia.
- It moves beyond single-marker inferences to a comprehensive analysis of macrophage states.
- The methodology facilitates the investigation of potential triggers without a priori assumptions about etiology.
