Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder

Attila Szabo; Kevin S O'Connell; Ibrahim A Akkouh; Thor Ueland; Ida E Sønderby; Sigrun Hope; Anne B Røe; Monica S Dønnum; Ingrid Sjaastad; Nils Eiel Steen; Torill Ueland; Linn Sofie Sæther; Jordi Requena Osete; Ole A Andreassen; Terje Nærland; Srdjan Djurovic

doi:10.1016/j.psychres.2024.116245

Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder

Psychiatry Res. 2024 Oct 30:342:116245. doi: 10.1016/j.psychres.2024.116245. Online ahead of print.

Authors

Attila Szabo¹, Kevin S O'Connell², Ibrahim A Akkouh³, Thor Ueland⁴, Ida E Sønderby⁵, Sigrun Hope⁶, Anne B Røe⁷, Monica S Dønnum⁸, Ingrid Sjaastad⁹, Nils Eiel Steen¹⁰, Torill Ueland¹¹, Linn Sofie Sæther¹¹, Jordi Requena Osete³, Ole A Andreassen¹², Terje Nærland¹³, Srdjan Djurovic¹⁴

Affiliations

¹ K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. Electronic address: [email protected].
² Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
³ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, building 25, Kirkeveien 166, Oslo 0450, Norway.
⁴ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁵ K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, building 25, Kirkeveien 166, Oslo 0450, Norway.
⁶ K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Neurohabilitation, Oslo University Hospital, Oslo, Norway; Department of Rare Disorders and Disabilities, Nevsom, Oslo University Hospital, Oslo, Norway.
⁷ St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
⁸ Department of Adult Habilitation, Akershus University Hospital, Oslo, Norway.
⁹ Department of Child and Adolescent Psychiatry, Vestre Viken Hospital Trust, Norway.
¹⁰ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹¹ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway.
¹² K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, University of Oslo, and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹³ K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Rare Disorders and Disabilities, Nevsom, Oslo University Hospital, Oslo, Norway.
¹⁴ K.G. Jebsen Center for Neurodevelopmental Disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, building 25, Kirkeveien 166, Oslo 0450, Norway; Department of Clinical Science, NORMENT, University of Bergen, Bergen, Norway. Electronic address: [email protected].

PMID: 39481220
DOI: 10.1016/j.psychres.2024.116245

Abstract

Background: Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified.

Methods: We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods.

Results: We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro.

Conclusion: Our results suggest a role for inflammasome dysregulation in ASD pathophysiology.

Keywords: Autism spectrum disorder; Cell adhesion factors; Inflammasome; Inflammation; Innate immunity; NLRP3.