The role of the vasculature in communicating systemic inflammation to the brain

Abstract

The central nervous system (CNS) undergoes profound physiological changes during systemic inflammation. Given the dense vascular network within the CNS, a signaling axis that involves the brain vasculature is an attractive route by which the host immune system evokes global brain responses. However, the CNS vasculature is unique because of the blood-brain barrier (BBB), which anatomically separates the circulating immune response from the brain parenchyma. This physical separation between blood and brain is essential to maintain a tightly controlled microenvironment for optimal neuronal survival and function. Despite serving as an important brain interface, the precise role of the BBB during systemic inflammation has remained unclear. The goal of this dissertation is to uncover new mechanisms by which the brain vasculature mediates immune-brain communication during systemic inflammation. First, in a model of systemic LPS inflammation we provide evidence that brain endothelial cells (BECs) are active and acute sensors of circulating inflammatory cues while the BBB remains intact. BEC activation subsequently evokes parenchymal cell responses by acting as a cellular relay point. Direct LPS sensing via TLR4 or integrated cytokine signaling are the suggested mechanisms behind LPS-mediated CNS responses. Through a combination of RNA sequencing, mouse genetics, and imaging studies we demonstrate that, despite the presence of circulating LPS, endothelial TLR4 is dispensable for both BEC activation and subsequent communication with microglia. Rather, systemic IL-1 was sufficient to activate BECs and mimic LPS-induced microglial reactivity suggesting that BECs may require IL-1 sensing to relay inflammatory messages to microglia. Next, we found that venous BECs (BvECs) uniquely express IL1R1 and sense circulating IL-1 to control LPS-induced microglial reactivity. Functional antibody blocking and BEC-specific IL1R1 knockout abrogate microglial LPS-induced activation. Finally, we found a distinct population of vessel associated microglia (VAM), which associate specifically with IL1R1-expressing BvECs under LPS-induced systemic inflammation. VAM exhibit a rapid response to systemic inflammation by undergoing a unique LPS-induced morphological reaction, flattening and elongating along IL1R1-expressing BvECs. Taken together, this work establishes an important role for the brain vasculature in communicating systemic inflammation while the BBB is intact. We identify a mechanism by which BvECs transform inflammatory cues from the systemic circulation to modulate microglial activation states through IL-1 signaling. Moreover, this IL-1-BvEC-microglia signaling axis establishes a functional role for BECs in controlling neuroimmune communication to the brain and may aid in efforts to develop therapeutic strategies to ameliorate the deleterious effects of systemic inflammation in the CNS.