Monocytic Subsets Impact Cerebral Cortex and Cognition: Differences Between Healthy Subjects and Patients With First-Episode Schizophrenia

Abstract

Monocytes are a highly heterogeneous population subcategorized into classical, intermediate and nonclassical subsets. How monocytes and their subsets may shape brain structures and functions in schizophrenia remains unclear. The primary goal of this cross-sectional study was to investigate monocytic subsets and their specific signature genes in regulation of cerebral cortical thickness and cognitive functions in first-episode schizophrenia (FES) patients. Whole-blood RNA sequencing of 128 FES patients and 111 healthy controls (HCs) were conducted and monocyte-specific differentially expressed genes were further analyzed. The MATRICS Consensus Cognitive Battery (MCCB) test, cortical neuroimaging and flow cytometric staining of peripheral blood monocytic subsets were performed among the participants. Significant changes in expressions of 54 monocytic signature genes were found in patients, especially for intermediate and nonclassical monocytic subsets with the most outstanding alterations being downregulated S100 Calcium Binding Protein A (S100A) and upregulated Interferon Induced Transmembrane Protein (IFITM) family members, respectively. Meanwhile, percentage of blood nonclassical monocytes was decreased in patients. Cortical thicknesses and MCCB performance were expectantly reduced and weaker intra-relationships among monocytic signature genes and cortices, respectively, were noted in patients compared to HCs. Monocytic genes were negatively associated with both cortical thicknesses and cognition in HCs, which was interestingly weakened or even reversed in patients, with nonclassical monocytic genes showing the greatest statistical significance. This study reveals that while monocytes may have negative effects on brain structure and cognition, the ameliorated phenomenon observed in schizophrenia may reflect an (mal)adaptive change of monocytes at early stage of the disorder.

Replenished microglia partially rescue schizophrenia-related stress response

“…We previously found that some FES patients had higher stress sensitivity ( Xuan et al, 2022 ) and reduced amounts of nonclassical monocytes along with altered signature gene expressions ( Chen et al, 2022 ) compared to HCs, implying their deficits in myeloid reprogramming. To relate the implications of repMg to a clinical setting, we explored a cohort from these FES patients and HCs.…”

“…After a week of transfer adaptation, the mice were subject to CUS/Ctr and CSF1Ri/Veh treatments ( Figure 1A and Supplementary Figure S2B ). CUS procedures, as previously described ( Cangalaya et al, 2020 ; Chen et al, 2022 ; Xuan et al, 2022 ), were followed. Briefly, mice were exposed to a variable sequence of seven mild and unpredictable stressors once per day (d) for eight consecutive weeks, including food and water deprivation overnight, rat odor and isolation overnight, restraint in a 50-ml tube for 2 h, wet bedding and tilted cage, stroboscopic illumination overnight, flipped light/dark exposure, and swimming at 18°C for 10 min.…”

“…We thereby performed a series of animal experiments to fine-map microglial properties in the prefrontal cortex (PFC) and hippocampus. We further studied those FES patients who showed heightened stress perception and innate immune activation in comparison to healthy subjects ( Chen et al, 2022 ; Xuan et al, 2022 ).…”

Systemic inflammatory biomarkers in Schizophrenia are changed by ECT administration and related to the treatment efficacy

“…Actually, the activation of monocytes has been consistently reported in schizophrenia, and first-episode schizophrenia had higher MCP-1 (Monocyte chemoattractant protein-1) both in the cerebrospinal fluid and blood [ 57 ]. Moreover, a recent study demonstrated atypical monocyte genes were negative correlated with cortical thickness and cognitive function in healthy controls, however, the correlation was attenuated in schizophrenia [ 58 ], highlighting the importance to explore monocyte subsets in the deterioration of cognitive function after ECT. Moreover, since peripheral systemic inflammation can lead to microglia activation in the brain, in vivo assessment of microglia activity before and after ECT by 18-kDa translocator protein (TSPO) PET can help to further clarify whether ECT treats schizophrenia by reducing neuroinflammation [ 59 , 60 ].…”

Monocyte subtype expression patterns in septic patients with diabetes are distinct from patterns observed in obese patients

“…Monocytes with CD16 + are generally elevated in a variety of diseases, including obesity, diabetes mellitus, cardiovascular disease, trauma, sepsis, autoimmunity, and psychosis ( 9 , 14 ). The precise onset of sepsis in obese patients with diabetes ( 5 ) is challenging, since we lack an understanding of the pathogenic mechanisms driving sepsis ( 15 ).…”