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<p>Astrocyte reactivity is a hallmark of neuroinflammatory diseases. Astrocytes contain functional circadian clocks that drive daily homeostatic rhythms, making them potential regulators of the transition from homeostatic to reactive states. However, it remains unclear whether neuroinflammatory conditions alter endogenous astrocyte clocks and whether these clock alterations contribute to pathway changes associated with reactivity. Here, we combined in vivo and in vitro lipopolysaccharide (LPS)-based neuroinflammation models with circadian profiling, chromatin analysis, and bulk RNA-sequencing of purified microglia and astrocytes. In vivo and in vitro, neuroinflammation reduced the amplitude of <i>Bmal1</i> and <i>Per1</i> rhythms and changed clock gene expression patterns across circadian time, while reactive markers gained rhythmic expression. In vitro, these clock changes occurred in astrocytes exposed to the inflammatory glial environment, but not after direct LPS treatment, indicating that paracrine glial signaling is the main driver. RNA-sequencing of microglia from the same neuroinflammatory glial cultures identified <i>Il1b</i> and <i>Tnf</i> as strong candidate mediators, and combined IL-1β/TNFα treatment was sufficient to suppress astrocyte clock gene expression and induce reactive marker expression. This clock suppression was accompanied by a modest reduction in BMAL1 protein but a stronger reduction in average BMAL1 occupancy at multiple clock target loci, including <i>Per1</i> and <i>Nr1d1</i>. To define BMAL1-dependent pathways in astrocytes, we compared gene expression in wild-type and <i>Bmal1</i>-deficient astrocytes, and then compared these changes with those observed under neuroinflammatory conditions. <i>Bmal1</i> loss alone did not reproduce the full inflammatory response. Instead, it identified a selective subset of the reactive astrocyte transcriptome, mainly involving suppression of cell-cycle and chromosome-segregation pathways with limited innate immune activation. Together, these findings identify astrocytic BMAL1 as a regulator of a selective pathway subset within reactive astrocytes in response to neuroinflammatory conditions.</p>

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Neuroinflammatory suppression of astrocytic BMAL1 defines a selective reactive astrocyte program

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Xingqi Meng,
  • Ming Ho Choi,
  • Xuebing Zhang,
  • Jin Young Kim

摘要

Astrocyte reactivity is a hallmark of neuroinflammatory diseases. Astrocytes contain functional circadian clocks that drive daily homeostatic rhythms, making them potential regulators of the transition from homeostatic to reactive states. However, it remains unclear whether neuroinflammatory conditions alter endogenous astrocyte clocks and whether these clock alterations contribute to pathway changes associated with reactivity. Here, we combined in vivo and in vitro lipopolysaccharide (LPS)-based neuroinflammation models with circadian profiling, chromatin analysis, and bulk RNA-sequencing of purified microglia and astrocytes. In vivo and in vitro, neuroinflammation reduced the amplitude of Bmal1 and Per1 rhythms and changed clock gene expression patterns across circadian time, while reactive markers gained rhythmic expression. In vitro, these clock changes occurred in astrocytes exposed to the inflammatory glial environment, but not after direct LPS treatment, indicating that paracrine glial signaling is the main driver. RNA-sequencing of microglia from the same neuroinflammatory glial cultures identified Il1b and Tnf as strong candidate mediators, and combined IL-1β/TNFα treatment was sufficient to suppress astrocyte clock gene expression and induce reactive marker expression. This clock suppression was accompanied by a modest reduction in BMAL1 protein but a stronger reduction in average BMAL1 occupancy at multiple clock target loci, including Per1 and Nr1d1. To define BMAL1-dependent pathways in astrocytes, we compared gene expression in wild-type and Bmal1-deficient astrocytes, and then compared these changes with those observed under neuroinflammatory conditions. Bmal1 loss alone did not reproduce the full inflammatory response. Instead, it identified a selective subset of the reactive astrocyte transcriptome, mainly involving suppression of cell-cycle and chromosome-segregation pathways with limited innate immune activation. Together, these findings identify astrocytic BMAL1 as a regulator of a selective pathway subset within reactive astrocytes in response to neuroinflammatory conditions.