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Blood–brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses

Significance Disruption of the blood–brain barrier (BBB) for drug delivery to the central nervous system (CNS) is achieved clinically through intracarotid artery hyperosmotic mannitol (ICAHM) infusions. However, ICAHM is often viewed as a simple drug delivery mechanism, and biological implications have been largely overlooked. This study demonstrates that BBB disruption by ICAHM generates a transient sterile neuroinflammatory response marked by increased production of cytokines, chemokines, and trophic factors leading activation of astrocytes, microglia, and macrophages. Additionally, unilateral ICAHM generates plasma increases in inflammatory molecules with evidence of sterile inflammation on the untreated contralateral hemisphere. These biological responses to ICAHM suggest its potential for immune modulation in several CNS pathologies. Intracarotid arterial hyperosmolar mannitol (ICAHM) blood–brain barrier disruption (BBBD) is effective and safe for delivery of therapeutics for central nervous system malignancies. ICAHM osmotically alters endothelial cells and tight junction integrity to achieve BBBD. However, occurrence of neuroinflammation following hemispheric BBBD by ICAHM remains unknown. Temporal proteomic changes in rat brains following ICAHM included increased damage-associated molecular patterns, cytokines, chemokines, trophic factors, and cell adhesion molecules, indicative of a sterile inflammatory response (SIR). Proteomic changes occurred within 5 min of ICAHM infusion and returned to baseline by 96 h. Transcriptomic analyses following ICAHM BBBD further supported an SIR. Immunohistochemistry revealed activated astrocytes, microglia, and macrophages. Moreover, proinflammatory proteins were elevated in serum, and proteomic and histological findings from the contralateral hemisphere demonstrated a less pronounced SIR, suggesting neuroinflammation beyond regions of ICAHM infusion. Collectively, these results demonstrate ICAHM induces a transient SIR that could potentially be harnessed for neuroimmunomodulation.