Optineurin Shapes Basal and LPS-Induced Transcriptomes in BV2 Microglia

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• The OPTN gene, encoding optineurin, is linked to neurodegenerative diseases involving microglial activation.
• Optineurin's precise function in microglia, particularly in inflammatory signaling and immune response, is not fully understood.

Purpose of the Study:

• To investigate the role of optineurin in microglial gene expression and inflammatory response.
• To characterize the impact of optineurin deficiency on the microglial transcriptome under basal and stimulated conditions.

Main Methods:

• Utilized CRISPR-Cas9 to create optineurin knockout (KO) BV2 microglia.
• Performed bulk RNA sequencing on wild-type and KO microglia under basal and LPS-stimulated conditions.
• Analyzed differential gene expression to identify optineurin-dependent pathways.

Main Results:

• Optineurin KO altered basal microglial transcriptome, downregulating interferon and antiviral pathways.
• LPS stimulation significantly reprogrammed wild-type microglia, while the response was blunted in optineurin KO cells.
• Optineurin deficiency led to impaired inflammatory gene induction and persistent cell cycle transcripts upon LPS stimulation, with unique DEG profiles.

Conclusions:

• Optineurin is a key regulator of the microglial transcriptome, essential for innate immune responses.
• Loss of optineurin reshapes microglial immune and cell cycle programs, offering insights into neuroinflammation in diseases like ALS and FTD.
• Provides a systems-level understanding of optineurin's role in microglia and its implications for neurodegeneration.