TY - JOUR
T1 - A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells
AU - Ormel, Paul R
AU - Böttcher, Chotima
AU - Gigase, Frederieke A J
AU - Missall, Roy D
AU - van Zuiden, Welmoed
AU - Camila Fernández Zapata, M
AU - Ilhan, Dilara
AU - de Goeij, Michelle
AU - Udine, Evan
AU - Sommer, Iris E C
AU - Priller, Josef
AU - Raj, Towfique
AU - Kahn, René S
AU - Hol, Elly M
AU - de Witte, Lot D
N1 - Copyright © 2020. Published by Elsevier Inc.
PY - 2020
Y1 - 2020
N2 - Different lines of evidence support a causal role for microglia in the pathogenesis of schizophrenia. However, how schizophrenia patient-derived microglia are affected at the phenotypic and functional level is still largely unknown. We used a recently described model to induce patient-derived microglia-like cells and used this to analyze changes in the molecular phenotype and function of myeloid cells in schizophrenia. We isolated monocytes from twenty recent-onset schizophrenia patients and twenty non-psychiatric controls. We cultured the cells towards an induced microglia-like phenotype (iMG), analyzed the phenotype of the cells by RNA sequencing and mass cytometry, and their response to LPS. Mass cytometry showed a high heterogeneity of iMG in cells derived from patients as well as controls. The prevalence of two iMG clusters was significantly higher in schizophrenia patients (adjusted p-value < 0.001). These subsets are characterized by expression of ApoE, Ccr2, CD18, CD44, and CD95, as well as IRF8, P2Y12, Cx3cr1 and HLA-DR. In addition, we found that patient-derived iMG show an enhanced response to LPS, with increased secretion of TNF-α. Further studies are needed to replicate these findings, to determine whether similar subclusters are present in schizophrenia patients in vivo, and to address how these subclusters are related to the increased response to LPS, as well as other microglial functions.
AB - Different lines of evidence support a causal role for microglia in the pathogenesis of schizophrenia. However, how schizophrenia patient-derived microglia are affected at the phenotypic and functional level is still largely unknown. We used a recently described model to induce patient-derived microglia-like cells and used this to analyze changes in the molecular phenotype and function of myeloid cells in schizophrenia. We isolated monocytes from twenty recent-onset schizophrenia patients and twenty non-psychiatric controls. We cultured the cells towards an induced microglia-like phenotype (iMG), analyzed the phenotype of the cells by RNA sequencing and mass cytometry, and their response to LPS. Mass cytometry showed a high heterogeneity of iMG in cells derived from patients as well as controls. The prevalence of two iMG clusters was significantly higher in schizophrenia patients (adjusted p-value < 0.001). These subsets are characterized by expression of ApoE, Ccr2, CD18, CD44, and CD95, as well as IRF8, P2Y12, Cx3cr1 and HLA-DR. In addition, we found that patient-derived iMG show an enhanced response to LPS, with increased secretion of TNF-α. Further studies are needed to replicate these findings, to determine whether similar subclusters are present in schizophrenia patients in vivo, and to address how these subclusters are related to the increased response to LPS, as well as other microglial functions.
U2 - 10.1016/j.bbi.2020.08.012
DO - 10.1016/j.bbi.2020.08.012
M3 - Article
C2 - 32798663
SN - 0889-1591
VL - 90
SP - 196
EP - 207
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -