Systemic Cell Adhesion Molecules in Severe Mental Illness: Potential Role of Intercellular CAM-1 in Linking Peripheral and Neuroinflammation,Biological Psychiatry

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Systemic Cell Adhesion Molecules in Severe Mental Illness: Potential Role of Intercellular CAM-1 in Linking Peripheral and Neuroinflammation
Biological Psychiatry ( IF 10.6 ) Pub Date : 2022-07-02 , DOI: 10.1016/j.biopsych.2022.06.029
Mashhood A Sheikh ₁ , Kevin S O'Connell ₂ , Tove Lekva ₁ , Attila Szabo ₃ , Ibrahim A Akkouh ₃ , Jordi Requena Osete ₃ , Ingrid Agartz ₄ , John A Engh ₅ , Dimitrios Andreou ₄ , Birgitte Boye ₆ , Erlend Bøen ₆ , Torbjørn Elvsåshagen ₂ , Sigrun Hope ₇ , Maren Caroline Frogner Werner ₂ , Inge Joa ₈ , Erik Johnsen ₉ , Rune A Kroken ₉ , Trine Vik Lagerberg ₂ , Ingrid Melle ₁₀ , Ole Kristian Drange ₁₁ , Gunnar Morken ₁₂ , Terje Nærland ₆ , Kjetil Sørensen ₁₂ , Arne E Vaaler ₁₃ , Melissa Authen Weibell ₈ , Lars T Westlye ₁₄ , Pål Aukrust ₁₅ , Srdjan Djurovic ₁₆ , Nils Eiel Steen ₁₀ , Ole A Andreassen ₁₀ , Thor Ueland ₁₇

Affiliation

Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT, University of Oslo, Oslo, Norway; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Vestfold Hospital Trust, Division of Mental Health and Addiction, Tønsberg, Norway.
NORMENT, University of Oslo, Oslo, Norway.
Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway.
Network for Clinical Psychosis Research, Division of Psychiatry, Stavanger University Hospital, Stavanger, Norway; Network for Medical Sciences, Faculty of Health, University of Stavanger, Stavanger, Norway.
Division of Psychiatry, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; NORMENT Centre of Excellence, Bergen, Norway.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; NORMENT, University of Oslo, Oslo, Norway.
Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway; Department of Psychiatry, Sørlandet Hospital HF, Kristiansand, Norway.
Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.

Background

Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells.

Methods

We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell–derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each).

Results

Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell–derived neurons from patients with SCZ.

Conclusions

Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

中文翻译：

严重精神疾病中的全身细胞粘附分子：细胞间 CAM-1 在连接外周和神经炎症中的潜在作用

背景

细胞粘附分子 (CAM) 通过促进炎症和免疫介导的反应以及介导血脑屏障信号，协调白细胞运输，并可能将严重精神疾病 (SMI) 患者的外周炎症和神经炎症联系起来。我们假设 CAM 在 SMI 中失调，并评估了不同血管和神经 CAM 的血浆水平。血浆中失调的 CAM 在体内白细胞和脑组织中以及在体外诱导多能干细胞中得到进一步评估。

方法

我们比较了精神分裂症 (SCZ) 谱系障碍的大型 SMI 样本中循环白细胞中不同血管（VCAM-1、ICAM-1、P-SEL）和神经（JAM-A、NCAD）CAM 的血浆可溶性水平（n = 895 ) 和情感障碍 ( n = 737) 和健康对照参与者 ( n = 1070) 控制年龄、性别、体重指数、C 反应蛋白和冷冻储存时间。我们还使用微阵列 ( n = 842) 评估了白细胞中ICAM1和编码 ICAM-1 受体的相关基因的信使 RNA 表达，以及来自背外侧前额叶皮质 ( n = 474）。在 SCZ 患者和健康对照参与者（每组n = 8）中评估了可溶性 ICAM-1 在诱导多能干细胞衍生的神经元和星形胶质细胞中的调节。

结果

我们的主要发现是 1) 与健康对照参与者相比，SMI 患者的可溶性 ICAM-1 增加；2)在 SMI 患者的循环白细胞中编码 ICAM-1 受体β链的ITGB2信使 RNA 增加， SCZ 中ICAM1的前额皮质信使 RNA 表达增加；3) 增强 SCZ 患者诱导的多能干细胞衍生神经元中可溶性 ICAM-1 的释放。