2. Academic Validation
  3. Microglial priming by IFN-γ involves STAT1-mediated activation of the NLRP3 inflammasome

Microglial priming by IFN-γ involves STAT1-mediated activation of the NLRP3 inflammasome

  • CNS Neurosci Ther. 2024 Oct;30(10):e70061. doi: 10.1111/cns.70061.
Haili He 1,  Xiaomei Zhang 2,  Hui He 2,  Gaojie Xu 2,  Liangyuan Li 1,  Chengyan Yang 1,  Yu-E Liu 1,  Zili You 2,  Jinqiang Zhang 1
Affiliations

Affiliations

  • 1 Resource Institute for Chinese and Ethnic Materia Medica, Guizhou University of Traditional Chinese Medicine, Guiyang, China.
  • 2 School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, China.
PMID: 39392762 DOI: 10.1111/cns.70061
Abstract

Background: Inflammatory and immune responses in the brain that contribute to various neuropsychiatric disorders may begin as microglial "priming". Interferon (IFN)-γ is known to cause microglial priming, but the mechanism is unclear.

Methods: We examined the effects of IFN-γ on gene expression, microglial activation, inflammatory and immune responses and activity of the NLRP3 inflammasome in primary microglia and in the brains of mice.

Results: Our results showed that treating microglial cultures with IFN-γ induced a hedgehog-like morphology and upregulated markers of microglial activation (CD86, CD11b) and pro-inflammatory molecules (IL-1β, IL-6, TNF-α, iNOS), while downregulating markers of microglial homeostasis (CX3CR1, CD200R1), anti-inflammatory molecules (MCR1, Arg-1) and Neurotrophic Factors (IGF-1, BDNF). IFN-γ also upregulated markers of NLRP3 inflammasome activation (NLRP3, Caspase-1, gasdermin D, IL-18). This particular transcriptional profiling makes IFN-γ-primed microglia with exaggerated responses upon lipopolysaccharide (LPS) stimulation. The level of NLRP3, Caspase-1, gasdermin D, IL-1β, IL-18, TNF-α and iNOS in microglia cultures treated with both IFN-γ and LPS were highest than with either one alone. Injecting IFN-γ into the lateral ventricle of mice induced similar morphological and functional changes in hippocampal microglia as in primary microglial cultures. The effects of IFN-γ on NLRP3 inflammasome and microglia from cultures or hippocampus were abolished when STAT1 was inhibited using fludarabin. Injecting mice with IFN-γ alone or together with LPS induced anxiety- and depression-like behaviors and impaired hippocampus-dependent spatial memory; these effects were mitigated by fludarabin.

Conclusions: IFN-γ primes microglia by activating STAT1, which upregulates genes that activate the NLRP3 inflammasome. Inhibiting the IFN-γ/STAT1 axis may be a way to treat neurodegenerative diseases and psychiatric disorders that involve microglial priming.

Keywords

NLRP3 inflammasome; STAT1; interferon‐gamma; lipopolysaccharide; microglial priming.

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