Integrative multi-omics analysis identifies coronin 1C as a potential mediator linking circadian rhythm disruption to neuroimmune dysregulation in ischemic stroke

May 2, 2026International immunopharmacology

Multi-omics study suggests coronin 1C links disrupted body clock to immune problems in stroke

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Abstract

Seven hub genes associated with circadian rhythm disruption were identified in ischemic stroke patients.

Circadian timing significantly affected stroke severity, with variations in infarct volume observed at different times of day.
High circadian rhythm disruption scores correlated with increased activation of CD8 T-cells and a decrease in M0 macrophages, suggesting a shift toward a proinflammatory immune response.
Single-cell analysis indicated activation of PD-1/PD-L1 signaling and Th17 polarization in T-cell subsets, which may reflect immune overactivation and exhaustion.
Knockdown of the hub gene coronin 1C (CORO1C) in microglia resulted in decreased secretion of inflammatory cytokines IL-6 and IFN-γ.
In vivo treatment with AAV-shCORO1C led to reduced CORO1C levels, decreased CD8 T-cell infiltration, enhanced expression of Claudin-5, and improved neurological function following stroke.

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INTRODUCTION: Circadian rhythm disruption (CRD) is a major driver of immune dysregulation; however, whether CRD promotes ischemic stroke (IS) progression through immune imbalance and the underlying molecular mechanisms remain unclear.

METHODS: Transcriptomic data from human IS brain tissues were analyzed to identify CRD associated regulators using machine-learning approaches. A CRD score model was constructed to quantify circadian disruption. Circadian timing-dependent stroke models were established to evaluate diurnal variation in stroke severity and gene rhythmicity in vivo. Single-cell transcriptomic analysis of peripheral blood mononuclear cell -derived scRNA-seq data was performed to characterize CRD-associated immune remodeling. Virtual gene knockdown analysis using the scTenifoldKnk framework, together with experimental validation including microglial gene silencing and T cell co-culture in vitro, as well as adeno-associated virus (AAV)-mediated gene intervention in a transient middle cerebral artery occlusion (tMCAO) model in vivo, were conducted to assess immunoregulatory effects and neurological recovery.

RESULTS: We identified seven hub genes associated with CRD in IS patients. Circadian timing significantly influenced stroke severity, with marked differences in infarct volume across Zeitgeber time points. In parallel, coronin 1C (CORO1C) exhibited rhythmic expression in the brain under physiological conditions, which was disrupted following ischemic stroke. High CRD scores were associated with enhanced CD8T-cell activation and reduced M0 macrophages, indicating a proinflammatory immune phenotype. Single-cell analysis revealed activation of PD-1/PD-L1 signaling and Th17 polarization within T-cell subsets, consistent with immune overactivation and functional exhaustion. Virtual knockdown analysis highlighted CORO1C as a central regulator linking neuronal and immune transcriptional programs. In microglia, CORO1C knockdown reduced IL-6 and IFN-γ secretion. In vivo, AAV-shCORO1C treatment decreased cerebral CORO1C expression, attenuated CD8T-cell infiltration and inflammatory signaling, enhanced Claudin-5 expression, improved neurological function, and promoted post-stroke recovery. + +

CONCLUSION: This study indicates that CORO1C acts as a pivotal regulator that mediates circadian rhythm disruption-driven immune dysregulation, thereby influencing stroke progression and neurological recovery.

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Integrative multi-omics analysis identifies coronin 1C as a potential mediator linking circadian rhythm disruption to neuroimmune dysregulation in ischemic stroke

Abstract

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