Choroid plexus inflammation in bipolar disorder
Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood–brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined.
To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD.
Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity.
Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology.
HIGHLIGHTS
• Elevated recruiting cytokines and reduced trophic cytokines in bipolar disorder choroid plexus.
• CCL2 and PLGF display opposite, condition-specific age associations.
• RNA-seq identifies oxidative stress, mitochondrial, and immune DEGs.
• NELL2, a CSF biomarker of BD, is downregulated in bipolar disorder choroid plexus.
• GSEA reveals immune activation, cellular stress, and junctional loss.
Web | DOI | Brain, Behavior, and Immunity | Open Access
Velez; Rahimian; Hehnly; Benson; Sacharczyk; Turecki; Mechawar; Lehtinen
Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood–brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined.
To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD.
Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity.
Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology.
HIGHLIGHTS
• Elevated recruiting cytokines and reduced trophic cytokines in bipolar disorder choroid plexus.
• CCL2 and PLGF display opposite, condition-specific age associations.
• RNA-seq identifies oxidative stress, mitochondrial, and immune DEGs.
• NELL2, a CSF biomarker of BD, is downregulated in bipolar disorder choroid plexus.
• GSEA reveals immune activation, cellular stress, and junctional loss.
Web | DOI | Brain, Behavior, and Immunity | Open Access