Peripheral HMGB1 is linked to O₃ pathology of disease-associated astrocytes and amyloid

INTRODUCTION: Ozone (O-3) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung-brain axis is implicated in O-3-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown. METHODS:The O-3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1(fl/fl)LysM-Cre(+) mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1). RESULTS: O-3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O-3-exposed Hmgb1(fl/fl)LysM-Cre(+) mice exhibited dysregulated DAA mRNA markers. DISCUSSION:Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O-3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology.