Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

Attila Szabo¹, Kevin S O'Connell², Thor Ueland³, Mashhood A Sheikh⁴, Ingrid Agartz⁵, Dimitrios Andreou⁶, Pål Aukrust⁷, Birgitte Boye⁸, Erlend Bøen⁹, Ole Kristian Drange¹⁰, Torbjørn Elvsåshagen¹¹, John Abel Engh¹², Sigrun Hope¹³, Margrethe Collier Høegh², Inge Joa¹⁴, Erik Johnsen¹⁵, Rune Andreas Kroken¹⁵, Trine Vik Lagerberg², Tove Lekva⁴, Ulrik Fredrik Malt¹⁶, Ingrid Melle¹⁷, Gunnar Morken¹⁸, Terje Nærland¹⁹, Vidar Martin Steen²⁰, Kjetil Sørensen²¹, Kirsten Wedervang-Resell², Melissa Auten Weibell¹⁴, Lars T Westlye²², Nils Eiel Steen², Ole Andreassen², Srdjan Djurovic²³

Affiliations

¹ 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. Electronic address: attila.szabo@medisin.uio.no.
² Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁵ Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁶ Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden.
⁷ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁸ Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Psychosomatic and Consultation-liason Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁹ Psychosomatic and Consultation-liason Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹⁰ Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway; Department of Psychiatry, St Olav University Hospital, Trondheim, Norway.
¹¹ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹² 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.
¹³ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway.
¹⁴ TIPS, Centre for Clinical Research in Psychosis, Stavanger University Hospital, Stavanger, Norway; Network for Medical Sciences, Faculty of Health, University of Stavanger, Stavanger, Norway.
¹⁵ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
¹⁶ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁷ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Department of Psychiatry, St Olav University Hospital, Trondheim, Norway.
¹⁹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Center for Neurodevelopmental Disorders, Oslo, Norway; Department of Rare Disorders and Disabilities, Oslo University Hospital, Oslo, Norway.
²⁰ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
²¹ Department of Psychiatry, St. Olav's University Hospital, Trondheim, Norway.
²² Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Center for Neurodevelopmental Disorders, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
²³ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: srdjan.djurovic@medisin.uio.no.

PMID: 34758379
DOI: 10.1016/j.bbi.2021.10.017

Free article

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

Attila Szabo et al. Brain Behav Immun. 2022 Jan.

Free article

. 2022 Jan:99:299-306.

doi: 10.1016/j.bbi.2021.10.017. Epub 2021 Nov 7.

Authors

Affiliations

¹ 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. Electronic address: attila.szabo@medisin.uio.no.
² Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁵ Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden; Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
⁶ Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden.
⁷ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁸ Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Psychosomatic and Consultation-liason Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁹ Psychosomatic and Consultation-liason Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹⁰ Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway; Department of Psychiatry, St Olav University Hospital, Trondheim, Norway.
¹¹ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹² 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.
¹³ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway.
¹⁴ TIPS, Centre for Clinical Research in Psychosis, Stavanger University Hospital, Stavanger, Norway; Network for Medical Sciences, Faculty of Health, University of Stavanger, Stavanger, Norway.
¹⁵ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
¹⁶ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁷ Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway; Department of Psychiatry, St Olav University Hospital, Trondheim, Norway.
¹⁹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G. Jebsen Center for Neurodevelopmental Disorders, Oslo, Norway; Department of Rare Disorders and Disabilities, Oslo University Hospital, Oslo, Norway.
²⁰ NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway; Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
²¹ Department of Psychiatry, St. Olav's University Hospital, Trondheim, Norway.
²² Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Center for Neurodevelopmental Disorders, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
²³ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: srdjan.djurovic@medisin.uio.no.

PMID: 34758379
DOI: 10.1016/j.bbi.2021.10.017

Abstract

Background: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients.

Methods: We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers.

Results: We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI.

Conclusions: Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

Keywords: Bipolar disorder; Cholesterol; Inflammasome; Inflammation; Interleukin-18; Psychosis; Schizophrenia.

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Inflammasome activation in psychosis - Consequence of peripheral dyslipidaemia or reflection of an inflammatory pathogenesis?
Humble MB, Bejerot S. Humble MB, et al. Brain Behav Immun. 2022 Mar;101:284-285. doi: 10.1016/j.bbi.2022.01.018. Epub 2022 Jan 20. Brain Behav Immun. 2022. PMID: 35065195 No abstract available.

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Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

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Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation

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