Neuroinflammatory suppression of astrocytic BMAL1 defines a selective reactive astrocyte program

Area of Science:

• Neuroscience
• Chronobiology
• Immunology

Background:

• Astrocyte reactivity is a key feature of neuroinflammatory diseases.
• Astrocytes possess circadian clocks that regulate daily rhythms.
• The impact of neuroinflammation on astrocyte clocks and reactivity is not well understood.

Purpose of the Study:

• To investigate whether neuroinflammation alters astrocyte circadian clocks.
• To determine if clock alterations contribute to astrocyte reactivity pathways.
• To identify the mechanisms driving these changes.

Main Methods:

• Utilized in vivo and in vitro lipopolysaccharide (LPS)-induced neuroinflammation models.
• Performed circadian profiling, chromatin analysis, and bulk RNA-sequencing of purified microglia and astrocytes.
• Investigated BMAL1-dependent pathways using wild-type and Bmal1-deficient astrocytes.

Main Results:

• Neuroinflammation reduced the amplitude of core clock gene rhythms (Bmal1, Per1) and altered clock gene expression patterns.
• Reactive astrocyte markers gained rhythmic expression.
• Paracrine glial signaling, mediated by IL-1β and TNFα, suppressed astrocyte clocks and induced reactivity.
• BMAL1 loss partially reproduced the reactive astrocyte transcriptome, highlighting its role in specific pathways.

Conclusions:

• Neuroinflammation significantly alters astrocyte circadian clock function.
• Glial paracrine signaling drives clock disruption and astrocyte reactivity.
• Astrocytic BMAL1 regulates a subset of reactive pathways, including cell-cycle and chromosome-segregation processes.