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The Role of the Nuclear Factor-?B Transcriptional Complex in Cortical Immune Activation in Schizophrenia.

ABSTRACT: BACKGROUND:Transcript levels for cytokines and the viral restriction factor interferon-induced transmembrane protein are markedly higher in the prefrontal cortex in schizophrenia. These gene products are regulated by the nuclear factor-?B (NF-?B) transcriptional complex. NF-?B activity, which requires the formation of NF-?B family member heterodimers, is regulated by activation receptors, kinases, and inhibitors. Whether any of these factors are altered in schizophrenia is not known. It is also unclear whether NF-?B-related disturbances reflect ongoing cortical immune activation or a long-lasting response to a prenatal immune-related insult. METHODS:Transcript levels for NF-?B pathway markers were assessed using quantitative polymerase chain reaction in the prefrontal cortex from 1) 62 matched pairs of schizophrenia and unaffected comparison subjects, 2) antipsychotic-exposed monkeys, and 3) adult mice exposed prenatally to maternal immune activation or in adulthood to the immune stimulant polyinosinic-polycytidylic acid. RESULTS:In schizophrenia subjects, but not antipsychotic-exposed monkeys, we found higher messenger RNA levels for 1) most NF-?B family members, 2) all NF-?B activation receptors, 3) several kinases, and 4) one inhibitor (I?B?) whose transcript level is itself regulated by NF-?B activity. A similar pattern of elevated NF-?B-related messenger RNA levels was seen in adult mice that received daily polyinosinic-polycytidylic acid injections, but not in adult mice subjected to maternal immune activation in utero. CONCLUSIONS:Higher NF-?B activity, evidenced by elevated transcript levels for NF-?B family members, activation receptors, and kinases, may contribute to increased markers of cortical immune activation in schizophrenia.

SUBMITTER: Volk DW

PROVIDER: S-EPMC6289758 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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The Role of the Nuclear Factor-κB Transcriptional Complex in Cortical Immune Activation in Schizophrenia.

Volk David W DW Moroco Annie E AE Roman Kaitlyn M KM Edelson Jessica R JR Lewis David A DA

Biological psychiatry 20180628 1

<h4>Background</h4>Transcript levels for cytokines and the viral restriction factor interferon-induced transmembrane protein are markedly higher in the prefrontal cortex in schizophrenia. These gene products are regulated by the nuclear factor-κB (NF-κB) transcriptional complex. NF-κB activity, which requires the formation of NF-κB family member heterodimers, is regulated by activation receptors, kinases, and inhibitors. Whether any of these factors are altered in schizophrenia is not known. It ...[more]

PMID: 30082065

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Project description:ObjectiveHigh-expression alleles of macrophage migration inhibitory factor (MIF) are linked genetically to the severity of systemic lupus erythematosus (SLE). The U1 small nuclear RNP (snRNP) immune complex containing U1 snRNP and anti-U1 snRNP antibodies, which are found in patients with SLE, activates the NLRP3 inflammasome, comprising NLRP3, ASC, and procaspase 1, in human monocytes, leading to the production of interleukin-1β (IL-1β). This study was undertaken to investigate the role of the snRNP immune complex in up-regulating the expression of MIF and its interface with the NLRP3 inflammasome.MethodsMIF, IL-1β, NLRP3, caspase 1, ASC, and MIF receptors were analyzed by enzyme-linked immunosorbent assay, Western blotting, quantitative polymerase chain reaction, and cytometry by time-of-flight mass spectrometry (CytoF) in human monocytes incubated with or without the snRNP immune complex. MIF pathway responses were probed with the novel small molecule antagonist MIF098.ResultsThe snRNP immune complex induced the production of MIF and IL-1β from human monocytes. High-dimensional, single-cell CytoF analysis established that MIF regulates activation of the NLRP3 inflammasome, including findings of a quantitative relationship between MIF and its receptors and IL-1β levels in the monocytes. MIF098, which blocks MIF binding to its cognate receptor, suppressed the production of IL-1β, the up-regulation of NLRP3, which is a rate-limiting step in NLRP3 inflammasome activation, and the activation of caspase 1 in snRNP immune complex-stimulated human monocytes.ConclusionThe U1 snRNP immune complex is a specific stimulus of MIF production in human monocytes, with MIF having an upstream role in defining the inflammatory characteristics of activated monocytes by regulating NLRP3 inflammasome activation and downstream IL-1β production. These findings provide mechanistic insight and a therapeutic rationale for targeting MIF in subgroups of lupus patients, such as those classified as high genotypic MIF expressers or those with anti-snRNP antibodies.

Dataset Information

The Role of the Nuclear Factor-?B Transcriptional Complex in Cortical Immune Activation in Schizophrenia.

Publications

The Role of the Nuclear Factor-κB Transcriptional Complex in Cortical Immune Activation in Schizophrenia.

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