NLRP3 inflammasome mediates astroglial dysregulation of innate and adaptive immune responses in schizophrenia

Attila Szabo; Ibrahim Akkouh; Jordi Requena Osete; Denis Reis de Assis; Elena Kondratskaya; Timothy Hughes; Thor Ueland; Ole A Andreassen; Srdjan Djurovic

doi:10.1016/j.bbi.2024.11.030

NLRP3 inflammasome mediates astroglial dysregulation of innate and adaptive immune responses in schizophrenia

Brain Behav Immun. 2024 Nov 29:S0889-1591(24)00719-0. doi: 10.1016/j.bbi.2024.11.030. Online ahead of print.

Authors

Attila Szabo¹, Ibrahim Akkouh², Jordi Requena Osete², Denis Reis de Assis², Elena Kondratskaya², Timothy Hughes², Thor Ueland³, Ole A Andreassen⁴, Srdjan Djurovic⁵

Affiliations

¹ Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway. Electronic address: attila.szabo@medisin.uio.no.
² Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³ Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Centre, University of Tromsø, Tromsø, Norway.
⁴ Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
⁵ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Centre for Neurodevelopmental Disorders, University of Oslo, Oslo, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.

PMID: 39617069
DOI: 10.1016/j.bbi.2024.11.030

Abstract

Mounting evidence indicates the involvement of neuroinflammation in the development of schizophrenia (SCZ), but the potential role of astroglia in this phenomenon remains poorly understood. We assessed the molecular and functional consequences of inflammasome activation using induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Screening protein levels in astrocytes at baseline identified lower expression of the NLRP3-ASC complex in SCZ, but increased Caspase-1 activity upon specific NLRP3 stimulation compared to CTRL. Using transcriptional profiling, we found corresponding downregulations of NLRP3 and ASC/PYCARD in both iPSC-derived astrocytes, and in a large (n = 429) brain postmortem case-control sample. Functional analyses following NLRP3 activation revealed an inflammatory phenotype characterized by elevated production of IL-1β/IL-18 and skewed priming of helper T lymphocytes (Th1/Th17) by SCZ astrocytes. This phenotype was rescued by specific inhibition of NLRP3 activation, demonstrating its dependence on the NLRP3 inflammasome. Taken together, SCZ iPSC-astrocytes display unique, NLRP3-dependent inflammatory characteristics that are manifested via various cellular functions, as well as via dysregulated innate and adaptive immune responses.

Keywords: Adaptive immunity; Astrocyte; Inflammasome; Inflammation; Innate immunity; NLRP3; Schizophrenia.