Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8
Interferon regulatory factor 8 (IRF8) is a transcription factor necessary for the maturation of microglia, as well as other peripheral immune cells. It also regulates the transition of microglia and other immune cells to a pro-inflammatory phenotype. is also a known risk gene for multiple sclerosis...
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Published in | The Journal of neuroscience Vol. 42; no. 32; pp. 6171 - 6185 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
10.08.2022
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Subjects | |
Online Access | Get full text |
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Summary: | Interferon regulatory factor 8 (IRF8) is a transcription factor necessary for the maturation of microglia, as well as other peripheral immune cells. It also regulates the transition of microglia and other immune cells to a pro-inflammatory phenotype.
is also a known risk gene for multiple sclerosis and lupus, and it has recently been shown to be downregulated in schizophrenia. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. Here, we show by RNAseq from
male and female mouse brains that several genes involved in regulation of neural activity are dysregulated. We then show that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to lethal seizures in male and female
mice. Finally, we identify that TNF-α is elevated specifically in microglia in the CNS, and genetic or acute pharmacological blockade of TNF-α in the
CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-α on neural circuits. Our data further suggest that neuronal function is impacted by loss of IRF8, a factor involved in neuropsychiatric and neurodegenerative diseases.
Here, we identify a previously unknown and key role for interferon regulator factor 8 (IRF8) in regulating neural excitability and seizures. We further determine that these effects on neural circuits are through elevated TNF-α in the CNS. As IRF8 has most widely been studied in the context of regulating the development and inflammatory signaling in microglia and other immune cells, we have uncovered a novel function. Further, IRF8 is a risk gene for multiple sclerosis and lupus, IRF8 is dysregulated in schizophrenia, and elevated TNF-α has been identified in a multitude of neurologic conditions. Thus, elucidating these IRF8 and TNF-α-dependent effects on brain circuit function has profound implications for understanding underlying, therapeutically relevant mechanisms of disease. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: P.A.F., L.C., L.F., D.S., C.A., V.D.-L., T.E.F., and D.P.S. designed research; P.A.F., S.C.B., L.C., L.F., C.A., V.D.-L., and T.E.F. performed research; P.A.F., S.C.B., L.C., L.F., C.A., and T.E.F. analyzed data; P.A.F. and D.P.S. wrote the first draft of the paper; P.A.F., S.C.B., L.C., D.S., C.A., R.K.S., and D.P.S. edited the paper; P.A.F., V.D.-L., T.E.F., and D.P.S. wrote the paper; D.P.S. and R.K.S. contributed unpublished reagents/analytic tools. S.C.B. and L.C. contributed equally to this work. |
ISSN: | 0270-6474 1529-2401 1529-2401 |
DOI: | 10.1523/JNEUROSCI.0601-22.2022 |