CD163+ perivascular macrophages in schizophrenia: a research framework for testing macrophage-related mechanisms.

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/