Loss of astrocytic Bmal1 promotes blood-brain barrier disruption and synaptic dysfunction during systemic inflammation

May 7, 2026Journal of neuroinflammation

Loss of a key daily rhythm protein in support brain cells may lead to blood-brain barrier damage and nerve connection problems during body-wide inflammation

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Abstract

Circadian rhythm disruption for three weeks markedly increased blood-brain barrier permeability in male mice.

Astrocytes contain the highest expression of core circadian clock genes among brain cell types.
Deletion of the Bmal1 gene in astrocytes led to significant increases in blood-brain barrier leakage and loss of pericytes after inflammation.
Bmal1-deficient astrocytes produced higher levels of the chemokine CXCL5, which may enhance neutrophil recruitment into the brain.
Blocking the CXCR2 receptor restored pericyte coverage and reduced blood-brain barrier disruption in astrocytic Bmal1 knockout mice.
Impairments in excitatory synaptic transmission were observed in Bmal1 knockout mice following systemic inflammation.

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Circadian rhythm disruption has been associated with the exaggerated inflammatory responses in peripheral tissues; however, its impact on neuroinflammation and blood-brain barrier (BBB) integrity remains unclear. Here, we identify the astrocytic circadian clock as a key regulator of BBB homeostasis during systemic inflammation. In a mouse model, circadian rhythm disruption for three weeks markedly increased BBB permeability in male mice, as evidenced by Evans blue leakage and myeloid cell infiltration into the brain parenchyma following lipopolysaccharide (LPS) challenge. Transcriptomic analyses using public datasets revealed that astrocytes exhibit the highest expression of core circadian clock genes among brain cell types. Accordingly, we generated tamoxifen-inducible, astrocyte-specific Bmal1-knockout (KO) mice. Deletion of Bmal1 in astrocytes significantly enhanced BBB leakage, astrogliosis and pericyte loss after LPS administration. Mechanistically, Bmal1-deficient astrocytes produced elevated levels of the chemokine CXCL5, which promoted CXCR2-dependent neutrophil recruitment into the brain. Pharmacological blockade of CXCR2 with SB225002 restored pericyte coverage and attenuated BBB disruption in astrocytic Bmal1 KO mice. Functionally, these mice exhibited impaired excitatory synaptic transmission following systemic inflammation, suggesting that astrocytic Bmal1 loss compromises neurovascular and synaptic integrity. Taken together, our findings demonstrate that astrocytic Bmal1 maintains BBB integrity and synaptic stability under inflammatory stress. This work also highlights astrocyte-intrinsic circadian regulation as a critical mechanism linking chemokine production to neurovascular vulnerability.