Abstract
This project investigated glial-based lymphatic (glymphatic) function and its role in a murine model of decompression sickness (DCS). DCS pathophysiology is traditionally viewed as being related to gas bubble formation from insoluble gas on decompression. However, a body of work implicates a role for a subset of inflammatory extracellular vesicles, 0.1 to 1 µm microparticles (MPs) that are elevated in human and rodent models in response to high gas pressure and rise further after decompression. Herein, we describe immunohistochemical and Western blot evidence showing that following high air pressure exposure, there are elevations of astrocyte NF-κB and microglial-ionized calcium-binding adaptor protein-1 (IBA-1) along with fluorescence contrast and MRI findings of an increase in glymphatic flow. Concomitant elevations of central nervous system-derived MPs coexpressing thrombospondin-1 (TSP) drain to deep cervical nodes and then to blood where they cause neutrophil activation. A new set of blood-borne MPs are generated that express filamentous actin at the surface that exacerbate neutrophil activation. Blood-brain barrier integrity is disrupted due to activated neutrophil sequestration that causes further astrocyte and microglial perturbation. When postdecompression node or blood MPs are injected into naïve mice, the same spectrum of abnormalities occur and they are blocked with coadministration of antibody to TSP. We conclude that high pressure/decompression causes neuroinflammation with an increased glymphatic flow. The resulting systemic liberation of TSP-expressing MPs sustains the neuroinflammatory cycle lasting for days.NEW & NOTEWORTHY A murine model of central nervous system (CNS) decompression sickness demonstrates that high gas pressure activates astrocytes and microglia triggering inflammatory microparticle (MP) production. Thrombospondin-expressing MPs are released from the CNS via enhanced glymphatic flow to the systemic circulation where they activate neutrophils. Secondary production of neutrophil-derived MPs causes further cell activation and neutrophil adherence to the brain microvasculature establishing a feed-forward neuroinflammatory cycle.