Interleukin-1 signaling in the blood-brain barrier influences the behavioral response to chronic social stress
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Abstract
Chronic stress is a major risk factor for depression, leading to systemic immune activation and neuroinflammation, both of which contribute to the development of depressive symptoms. The blood-brain barrier (BBB), with endothelial cells as a central component, plays a crucial role in maintaining central nervous system (CNS) homeostasis by regulating the exchange of molecules and immune cells between the blood and CNS. However, the precise impact of chronic stress on BBB function and whether BBB components contribute to the establishment of depression-like behavior following stress remain unclear. Interleukin-1 (IL-1), a key pro-inflammatory cytokine, plays a central role in the development of stress-induced behavioral changes. Its receptor, IL-1R1, is primarily expressed by BBB endothelial cells (BECs) in the CNS, but its expression is restricted to a small subset of these cells under steady-state conditions. Chronic social defeat (CSD) stress has been shown to upregulate IL-1R1 expression on BECs, potentially driving BBB activation during stress. Although systemic endothelial IL 1R1 deletion has been shown to alleviate stress-induced behavioral symptoms, it remains unclear whether IL-1 signaling specifically in BECs mediates these effects.
Using the Slco1c1-CreERT2 mouse strain to delete IL-1R1 selectively in BECs, this study aimed to investigate the role of IL-1 signaling in BECs during CSD and its contribution to depression-like behavior. Here, we show that IL-1 signaling in BECs is critical for mediating stress-induced behavioral dysfunction, as conditional deletion of IL-1R1 in BECs increased stress resilience and ameliorated behavioral changes following CSD. We found that IL-1R1⁺ BECs constitute a small, distinctly activated BEC subset under steady-state conditions. CSD stress further increased IL-1R1 expression on BECs, which was essential for their activation during stress. Notably, IL-1 signaling in BECs influenced behavior independently of peripheral immune cell infiltration or neuroinflammation, suggesting that alternative mechanisms are involved.
While IL-1 signaling is a well-established key regulator of chronic stress responses, our results demonstrate that this effect is specifically mediated through BECs, highlighting the importance of the BBB in the chronic stress response. Taken together, our findings suggest that targeting IL-1 signaling in BECs could be a promising strategy for mitigating stress-induced neurovascular dysfunction and its associated behavioral consequences.