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

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• SCZ astrocytes express lower levels of NLRP3-ASC corresponding to similar expression patterns in postmortem brain samples. • Higher activity of Caspase-1 upon inflammasome stimulation relative to CTRL in iPSC-astrocytes. • Skewed Th1 and Th17 lymphocyte activation capacity by SCZ astrocytes upon specific NLRP3 inflammasome activation. • Decreased resting basal glycolysis and a cell-intrinsic inability in regulating it in SCZ astroglia. 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.

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