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

Mashhood A Sheikh; Kevin S O'Connell; Tove Lekva; Attila Szabo; Ibrahim A Akkouh; Jordi Requena Osete; Ingrid Agartz; John A Engh; Dimitrios Andreou; Birgitte Boye; Erlend Bøen; Torbjørn Elvsåshagen; Sigrun Hope; Maren Caroline Frogner Werner; Inge Joa; Erik Johnsen; Rune A Kroken; Trine Vik Lagerberg; Ingrid Melle; Ole Kristian Drange; Gunnar Morken; Terje Nærland; Kjetil Sørensen; Arne E Vaaler; Melissa Authen Weibell; Lars T Westlye; Pål Aukrust; Srdjan Djurovic; Nils Eiel Steen; Ole A Andreassen; Thor Ueland

doi:10.1016/j.biopsych.2022.06.029

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

Biol Psychiatry. 2023 Jan 15;93(2):187-196. doi: 10.1016/j.biopsych.2022.06.029. Epub 2022 Jul 2.

Authors

Mashhood A Sheikh¹, Kevin S O'Connell², Tove Lekva¹, Attila Szabo³, Ibrahim A Akkouh³, Jordi Requena Osete³, Ingrid Agartz⁴, John A Engh⁵, Dimitrios Andreou⁴, Birgitte Boye⁶, Erlend Bøen⁶, Torbjørn Elvsåshagen², Sigrun Hope⁷, Maren Caroline Frogner Werner², Inge Joa⁸, Erik Johnsen⁹, Rune A Kroken⁹, Trine Vik Lagerberg², Ingrid Melle¹⁰, Ole Kristian Drange¹¹, Gunnar Morken¹², Terje Nærland⁶, Kjetil Sørensen¹², Arne E Vaaler¹³, Melissa Authen Weibell⁸, Lars T Westlye¹⁴, Pål Aukrust¹⁵, Srdjan Djurovic¹⁶, Nils Eiel Steen¹⁰, Ole A Andreassen¹⁰, Thor Ueland¹⁷

Affiliations

¹ Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway.
² Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ 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.
⁴ 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.
⁵ 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.
⁶ NORMENT, University of Oslo, Oslo, Norway.
⁷ Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway.
⁸ 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.
⁹ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway; NORMENT Centre of Excellence, Bergen, Norway.
¹⁰ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; NORMENT, University of Oslo, Oslo, Norway.
¹¹ 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.
¹² Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway.
¹³ 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.
¹⁴ 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.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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. Electronic address: thor.ueland@medisin.uio.no.

PMID: 36182530
DOI: 10.1016/j.biopsych.2022.06.029

Abstract

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.

Keywords: Affective disorder; Blood-brain barrier; Cell adhesion molecule; Immune activation; Inflammation; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Adhesion Molecules / metabolism
Humans
Intercellular Adhesion Molecule-1*
Neuroinflammatory Diseases
RNA, Messenger / metabolism
Schizophrenia*
Vascular Cell Adhesion Molecule-1

Substances

Intercellular Adhesion Molecule-1
Cell Adhesion Molecules
Vascular Cell Adhesion Molecule-1
RNA, Messenger